JP2020063264A - Methods of increasing tonic inhibition and treating secondary insomnia - Google Patents

Abstract

To provide a method of increasing tonic inhibition of neurons in a human subject with a neurodegenerative disease, a neurogenetic disorder, or a central nervous system disorder.SOLUTION: A method of increasing tonic inhibition of neurons in a human subject includes administering a pharmaceutical composition comprising an effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient.SELECTED DRAWING: None

Description

  The technical field of this invention is generally 4,5,6,7-tetrahydroisoxazolo () for treating diseases or disorders characterized by secondary insomnia and / or deficiencies or defects in persistent depression. 5,4-c) Pyridin-3-ol (THIP), a derivative thereof, or a method of using a composition containing a pharmaceutically acceptable salt thereof.

  Although many advances have been made, treatments for neurodegenerative and neurogenic disorders remain inadequate.

Some neurological disorders are associated with underlying pathophysiology, for example, Fragile X syndrome and Angelman syndrome are associated with loss of sustained inhibition in certain tissues of the brain. Some neurological disorders are associated with symptoms. For example, various neurodegenerative diseases are characterized by a wide range of symptoms, but many diseases and disorders are associated with one or more sleep-related disorders such as insomnia, interrupted sleep and altered sleep architecture. (Jennum et al., "CHAPTER 39: Sleep disorders in neurodegenerative disorders and stroke", European Handbook of Neurological Management , Volume 1, 2nd Edition (Ed. Gilhus et al. Blackwell Publishing Ltd. 2011)).

  For diseases such as Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Fragile X syndrome and Angelman syndrome, treatment is very limited and no cure exists. Therefore, there is a need for additional therapeutic options for treating neurodegenerative diseases, neurogenic and other central nervous system disorders.

  Accordingly, one object of the present invention is to provide a method of treating and preventing secondary insomnia in patients with neurological disorders.

  Another object of the invention is to provide a method of increasing tonic inhibition in a patient in need of increased tonic inhibition.

SUMMARY OF THE INVENTION A method of increasing persistent inhibition of neurons in a patient, particularly a patient with Fragile X Syndrome or Angelman Syndrome, is provided. Provided are methods of treating secondary insomnia in patients with neurodegenerative diseases or central nervous system disorders. The method typically increases slow-wave sleep (SWS) and / or slow-wave activity (SWA), normalizes sleep architecture, and causes secondary insomnia to increase persistent inhibition in neurons in the patient. Increase non-rapid (non-rapid eye movement) (NREM) sleep, increase sleep continuity, increase non-REM (NREM) sleep, increase sleep continuity, NREM Delta activity within, increase or improve total sleep time (TST), increase or improve sleep efficiency, reduce total wake time (TAA), reduce wake frequency (NWA), continuous sleep latency An effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4) for shortening (LPS) or reducing alertness (WASO), or any combination thereof in a patient. -c) Pyridine-3-ol (THIP) or its derivative and a pharmaceutically acceptable carrier or excipient Administering to the patient a pharmaceutical composition comprising.

  In certain embodiments, the patient suffering from secondary insomnia has Parkinson's disease (PD) or PD-related disorders, Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or Alzheimer's disease. Have.

  In the most preferred embodiment, THIP or a derivative thereof is THIP or a pharmaceutically acceptable salt thereof. THIP or a derivative thereof can be the sole active agent in the pharmaceutical composition or it can be one of two or more active agents. The pharmaceutical composition is formulated for sustained release. The pharmaceutical composition can be administered transdermally, for example, by contacting a patient's skin with a transdermal patch containing the pharmaceutical composition. In certain embodiments, the daily dose of THIP or a derivative thereof is about 2.5 mg to 50 mg / day.

Detailed description
I. Definitions The term "carrier" or "excipient" as used herein means an organic or inorganic ingredient, natural or synthetic inactive ingredient in the formulation, in combination with one or more active ingredients.

  As used herein, the term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.

  As used herein, the term “effective amount” or “therapeutically effective amount” means a dose sufficient to ameliorate one or more symptoms of the disorder, disease or condition being treated. The exact dosage will depend on a variety of factors such as the patient dependent variable (eg age, immune system health, etc.), the disease or disorder being treated and the route of administration and the pharmacokinetics of the agent being administered.

  As used herein, the term "prevention" or "preventing" refers to the cessation of a particular symptom of a disease or disorder, the reduction or prevention of one or more symptoms of the disease or disorder, the reduction of the severity of the disease or disorder. , At risk of one or more symptoms caused by a disease or disorder, or to predispose the disease or disorder to cause complete elimination of the disease or disorder, or stabilization or delay of development or progression of the disease or disorder. It means to administer the composition to a patient or body having.

II. Compositions containing gaboxadol or its derivatives 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridine-for treating secondary insomnia, disturbed sleep architecture, or a combination thereof in a patient Disclosed are methods using 3-ol (THIP), its derivatives, or pharmaceutically acceptable salts thereof. In some embodiments, the patient has or is at risk of developing a neurodegenerative disease or central nervous system disorder. In the most preferred embodiment, the patient suffers from secondary insomnia and / or disturbed sleep architecture due to neurodegenerative diseases or central nervous system disorders. As described in more detail below, the method typically comprises increasing an effective amount of an effective amount of 4,5,6, for increasing slow wave sleep, normalizing sleep architecture, or a combination thereof. 7-Tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP), a derivative thereof, or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof. In some embodiments, the clinical symptoms of neurodegenerative disease or central nervous system disorder are reduced.

  4,5,6,7-Tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP), a derivative thereof, or a pharmaceutically acceptable salt thereof is used to increase long-lasting inhibition. Methods of use are also provided. The method can be used to increase persistent depression in a patient having a disease or disorder characterized by a deficiency or deficiency of persistent depression, eg, Fragile X Syndrome or Angelman Syndrome.

A. 4,5,6,7-Tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP)
The compositions for use in the methods of treating secondary insomnia disclosed include 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (also referred to as THIP and gaboxadol. ), A derivative thereof, or a pharmaceutically acceptable salt thereof, or a structurally related compound. THIP, as well as derivatives and structurally related compounds, and methods of making the same are known in the art. See, eg, US Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005/094820, each of which is incorporated herein by reference in its entirety. Particularly preferred compounds are discussed in more detail below.

[4,5,6,7-テトラヒドロイソオキサゾロ(5,4-c)ピリジン-3-オール(THIP)]
で示される化合物、またはその互変異性体、異性体、エピマーもしくはジアステレオマーである。 In some embodiments, the compound has the formula ((Ia)):

[4,5,6,7-Tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP)]
Or a tautomer, isomer, epimer or diastereomer thereof.

THIP is a very potent GABA agonist that is well tolerated, has very specific activity and is inactive as a GABA uptake inhibitor. Gaboxadol is a selective extrasynaptic GABA _A agonist (SEGA) (Deacon et al., Sleep, 30 (3): 281-287 (2007)). GABA _A receptors are pentameric transmembrane proteins with five subunits forming the central anion channel. Gaboxadol binds to the interface between the α and β subunits, which is the same site where endogenous GABA ligands bind. Gaboxadol directly affects chlorine conductance independent of GABA and can directly activate extrasynaptic δ-containing receptors via interaction with GABA binding sites. Extrasynaptic δ-containing receptors are predominantly expressed in the thalamus, cerebral cortex, and limbic system. These brain regions are involved in regulating sleep and synchronizing cortical activity.

  The selective activity of compound (Ia) is believed to be due to the specific position of the nitrogen atom of the 6-membered ring in relation to the acidic hydroxy group of the 5-membered ring.

[式中、R”は、水素、アセチルまたは一般式(II)：

(式中、R₅は、C_1-8アルキル；フェニル；4位にてハロゲン、低級アルコキシまたは低級アルキルで置換されたフェニル；ベンジルまたはフェニルエチルまたはなどのフェニルアルキル(ここで、フェニル基は、4位にてハロゲン、低級アルコキシまたは低級アルキルで置換されてもよい)で示される基]
で示される化合物およびその塩。 Thus, the compound (Ia) and its derivatives, especially the derivatives which, upon administration, are decomposed in situ to give the parent compound (Ia), in particular the general formula (I):

[Wherein R "is hydrogen, acetyl or the general formula (II):

(Wherein R ₅ is C _1-8 alkyl; phenyl; phenyl substituted at the 4-position with halogen, lower alkoxy or lower alkyl; benzyl or phenylethyl or phenylalkyl such as (wherein the phenyl group is A group represented by 4-position, which may be substituted with halogen, lower alkoxy or lower alkyl)
And a salt thereof.

R's that are not hydrogen, in that they can enhance the compound's ability to cross the blood-brain barrier, are then cleaved in situ to give the parent compound,
It is believed that it is possible to enhance the entry of compounds into the brain. In addition, the long-term effect of compound (Ia) can be obtained through the in-situ decomposition of the compound in which R ″ is not hydrogen to form the parent compound.

で示される互換異性体で存在しうる。式(I)は、この互変異性体(I')および2つの互変異性体の混合物も包含すると理解されるべきである。 "Lower alkyl", "lower alkoxy" and "lower alkyloxy" are compounds of the general formula (I) which represent such groups containing 1 to 6 carbon atoms, preferably 1 to 4 atoms. Is the formula (I '):

It may exist in the compatible isomer shown by. It should be understood that formula (I) also includes this tautomer (I ′) and mixtures of the two tautomers.

  Examples of compounds of general formula (I) in which R ″ is not hydrogen are: 6-acetyl-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine- 3-ol, methyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-6-carboxylate, ethyl 3-hydroxy-4,5,6,7-tetrahydroiso Oxazolo [5,4-c] pyridine-6-carboxylate, tert.butyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-6-carboxylate, phenyl 3-Hydroxy-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-6-carboxylate, 4-chlorophenyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo [ 5,4-c] Pyridine-6-carboxylate, 4-methoxyphenyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-6-carboxylate, benzyl 3- Hi Droxy-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-6-carboxylate and its salts with bases.

  Derivatives of THIP are known in the art. See, for example, U.S. Pat. No. 4,353,910.

(III)
[式中、Rは、1〜17個の炭素原子を有する分枝または非分枝のアルキル基；低級アルキル、低級アルキルオキシおよびハロゲンから選ばれる1または2個の基で任意に置換されたフェニル基；フェニルアルキル基；低級アルキルオキシ基；または-NHR₁基(ここで、R₁は、水素、低級アルキル、フェニルまたはシクロヘキシルである)]
で示される化合物ならびにその医薬的に許容しうる酸付加塩である。 Preferred derivatives have the formula:

(III)
[Wherein, R is a branched or unbranched alkyl group having 1 to 17 carbon atoms; phenyl optionally substituted with 1 or 2 groups selected from lower alkyl, lower alkyloxy and halogen. Group; phenylalkyl group; lower alkyloxy group; or -NHR ₁ group (wherein R ₁ is hydrogen, lower alkyl, phenyl or cyclohexyl)]
And a pharmaceutically acceptable acid addition salt thereof.

  The compounds of formula (III) as well as their pharmaceutically acceptable acid addition salts show the same level of GABA-related activity as the compound THIP and some compounds also show a prolonged effect compared to THIP . Furthermore, they show a pronounced analgesic and muscle tone-relieving effect.

  Examples of pharmaceutically acceptable salts of compounds of the disclosed formulas include salts with inorganic acids. Examples of the salt represented by the formula include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, organic carboxylic acids such as acetic acid, propionic acid, glycolic acid, malonic acid, succinic acid, Organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, glucuronic acid, benzoic acid, pamoic acid and the like, or organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid. An acid addition salt thereof, such as a salt with, which can be prepared by a procedure known per se, for example, by adding the acid to a base, preferably a solvent. The compounds of the formula include metal salts such as sodium, potassium, calcium or aluminum salts, and ammonium and substituted ammonium salts such as salts of amines such as triethylamine, triethanolamine, ethylpiperidine, procaine and dibenzylamine. It is possible to form pharmaceutically acceptable salts with bases, such as

  Throughout this specification "THIP or a derivative thereof" refers to a base (zwitterion), a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt, a hydrate or solvate of a base or salt. , And anhydrous, and forms of the compound such as amorphous or crystalline forms.

B. Formulations The disclosed compounds can be formulated into pharmaceutical compositions. The pharmaceutical composition may be administered parenterally (intramuscularly, intraperitoneally, intravenously (IV) or subcutaneously), enterally, transdermally (using passive or iontophoresis or electroporation) or transmucosal. It can be administered by the route of administration (nasal, pulmonary, vaginal, rectal or sublingual) or by means of bioerodible inserts and can be formulated into suitable dosage forms for each route of administration.
The composition can be administered systemically.

  The drug can be formulated for immediate release, sustained release, or modified release. Delayed release dosage forms are those that release the drug (s) at a time other than immediately after administration. Sustained release dosage forms allow the frequency of administration to be reduced by at least 1/2 compared to conventional dosage forms (e.g., as solutions or conventional solid dosage forms with immediate drug release). It is a thing. Controlled release dosage forms have drug release characteristics selected over time and / or location to achieve therapeutic or expedient goals not provided by conventional dosage forms such as solution, ointment, or immediate dissolution dosage forms. It is a dosage form. Delayed release and sustained release dosage forms and combinations thereof are types of modified release dosage forms.

  The formulation is manufactured using a medically acceptable "carrier" of materials that are considered safe and effective and can be administered to an individual without causing undesired biological side effects or unwanted interactions. A "carrier" is any ingredient present in a pharmaceutical formulation except the active ingredient (s). The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers and coating compositions.

"Carrier" also includes all components of the coating composition that may include plasticizers, pigments, colorants, stabilizers, glidants. Delayed release dosage formulations provide information on carriers, materials, devices and methods for the manufacture of tablets and capsules, as well as delayed release dosage forms of tablets, capsules and granules, "Pharmaceutical dosage form tablets", eds Liberman et. Al. (New York, Marcel Dekker, Inc., 1989), "Remington-The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms". . and drug delivery systems ^{", 6 th Edition, Ansel et.al,} (Media, PA: Williams and Wilkins, 1995) can be prepared as described in references such as.

  The compound can be administered to the subject with or without the help of a delivery vehicle. Suitable delivery vehicles for the compounds are known in the art and can be selected to suit a particular active agent. For example, in some embodiments, the active agent is incorporated into, encapsulated in, or attached to nanoparticles, microparticles, micelles, synthetic lipoprotein particles, or carbon nanotubes. For example, the composition can be incorporated into a vehicle such as a polymeric microparticle that provides controlled release of the active agent. In some embodiments, drug release is controlled by degradation of the polymer particles by diffusion and / or hydrolysis and / or enzymatic degradation of the active agent from the microparticles.

  Suitable polymers include ethyl cellulose and other natural or synthetic cellulose derivatives. Polymers that slowly dissolve to form gels in an aqueous environment, such as hydroxypropylmethylcellulose or polyethylene oxide, may also be suitable as materials for the drug-containing microparticles or particles. Other polymers include polyanhydrides such as polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide) (PLGA), poly-3-hydroxybutyrate (PHB) and copolymers thereof, poly ( Ester anhydride), polyhydroxy acid, poly-4-hydroxybutyrate (P4HB) and its copolymers, polycaprolactone and its copolymers, and combinations thereof, but are not limited thereto. In some embodiments, both agents are incorporated into the same particle and are formulated to be released over different times and / or over different time periods. For example, in some embodiments, one of the drugs is completely released from the particles before the release of the second drug begins. In other embodiments, release of the first drug is initiated, followed by release of the second drug before all of the first drug is released. In still other embodiments, both agents are released simultaneously over the same time period or different time periods.

1. The pharmaceutical compound for parenteral administration and its pharmaceutical composition can be administered by parenteral injection in an aqueous solution. The formulation may be in the form of a suspension or emulsion. Generally, a pharmaceutical composition is provided that comprises an effective amount of the active agent, optionally containing a pharmaceutically acceptable diluent, preservative, solubilizer, emulsifier, adjuvant and / or carrier. Such compositions include diluent sterile water, various buffer contents (eg Tris-HCl, acetate, phosphate), pH and ionic strength buffered saline; and, optionally, a surfactant and Solubilizers (eg TWEEN® 20, TWEEN® 80, also referred to as POLYSORBATE® 20 or 80); antioxidants (eg ascorbic acid, sodium metabisulfite); and preservatives (Eg, thimerosol, benzyl alcohol) and bulking agents (eg, lactose, mannitol). Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. The formulation can be lyophilized and redissolved / resuspended immediately before use. The formulation can be sterilized by, for example, filtration through a bacterial retention filter, incorporation of a sterilant into the composition, irradiation of the composition, or heating of the composition.

2. Oral Immediate Release Formulations Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups and lozenges. Tablets may be made using compression or molding techniques well known in the art. Gelatin capsules or non-gelatin capsules can be manufactured using techniques well known in the art as hard or soft capsule shells capable of encapsulating liquid, solid and semi-solid fill materials.

  Examples of suitable coating materials include cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate and hydroxypropylmethyl cellulose acetate succinate; polyvinyl acetate phthalates, acrylic acid polymers and copolymers, and trade names. Examples include, but are not limited to, methacrylic resins, zein, shellac, and polysaccharides commercially available from Eudragit® (Roth Pharma, Westerstadt, Germany).

  In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers and surfactants.

  Any pharmaceutically acceptable excipient present in drug-containing tablets, beads, granules or particles may include diluents, binders, lubricants, disintegrants, colorants, stabilizers and surfactants. However, the present invention is not limited to these. Diluents, also referred to as "fillers," are typically needed to increase the bulk of a solid dosage form, so as to provide a practical size for compression of tablets or formation of beads and granules. Suitable diluents include dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, dioxide. Examples include, but are not limited to, silicon, titanium oxide, magnesium aluminum silicate and powdered sugar.

  Binders are used to impart cohesive qualities to a solid dosage formulation, thus ensuring that the tablets or beads or granules remain intact after formation of the dosage form. Suitable binders include starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycols, waxes; natural and synthetic gums such as gum arabic, gum tragacanth, sodium alginate; hydroxy. Cellulose, including propylmethylcellulose, hydroxypropylcellulose, ethylcellulose; and veegum, and acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methylmethacrylic acid copolymers, aminoalkylmethacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone Synthetic polymers such as, but not limited to.

  Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc and mineral oil.

  Disintegrants are used to facilitate disintegration or "degradation" of the dosage form after administration, and commonly include starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, as disintegrants. Examples include, but are not limited to, cross-linked polymers such as pregelatinized starch, clay, cellulose, arginine, gums or cross-linked PVP (Polyplasdone XL, GAF Chemical Corp).

  Stabilizers are used to inhibit or delay drug degradation reactions including, for example, oxidation reactions.

  Surfactants may be anionic, cationic, amphoteric or nonionic surfactants. Suitable anionic surfactants include, but are not limited to, those containing carboxylates, sulfonates and sulfates. Examples of anionic surfactants include long-chain alkylsulfonates sodium, potassium, ammonium, and alkylarylsulfonates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates such as sodium dodecylbenzenesulfonate; bis- And sodium dialkylsulfosuccinates such as (2-ethylthioxyl) sodium sulfosuccinate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene and coconut amine. Not a thing. Examples of nonionic surfactants are ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octyl phenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER (registered trademark) 401, stearoyl monoisopropanol Amides, and polyoxyethylene hydrogenated tallow amides. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

  If desired, tablets, bead granules or particles may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents and preservatives.

3. Sustained Release Dosage Form `` Sustained release formulations are generally diffused as described, for example, in Remington-The science and practice of pharmacy '' (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). Or manufactured as an infiltration system. Diffusion systems typically consist of two types of devices, reservoirs and matrices, which are well known and described in the art. Matrix devices are generally manufactured by compressing the drug into a tablet form with a slowly dissolving polymeric carrier. The three main types of materials used in the manufacture of matrix devices are insoluble plastics, hydrophilic polymers and aliphatic compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride and polyethylene. Hydrophilic polymers include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, Carbopol 934, polyethylene oxide. Aliphatic compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate.

  Alternatively, sustained release formulations may be prepared using an osmotic system or by applying a semipermeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low and high permeability coating materials in appropriate proportions.

  Devices with different drug release mechanisms described above can be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, granules and the like.

  The immediate release portion applies the immediate release layer over the sustained release core using a coating or compression process, or in a multi-unit system such as a capsule containing sustained release and immediate release beads. It can be added to a release system.

  Sustained release tablets containing hydrophilic polymers are made by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually include polymers, diluents, binders and lubricants, as well as the active pharmaceutical ingredient. Common diluents include many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, inert powdered substances such as flour and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and lactose, fructose, and sugars such as glucose. Natural and synthetic gums including acacia, alginates, methylcellulose and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, ethyl cellulose and waxes can also serve as binders. A lubricant is required in the tablet formulation to prevent the tablets and punches from sticking to the die. The lubricant is selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

  Sustained-release tablets containing a wax material are generally manufactured using methods known in the art such as direct mixing, solidification, and water dispersion. In the coagulation method, the drug is mixed with the wax material, spray coagulated or coagulated, screened and processed.

Four. Delayed Release Dosage Form A delayed release formulation is made by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

  Delayed release dosage units can be prepared, for example, by coating the drug or drug-containing composition with a selected coating material. The drug-containing composition is, for example, a tablet for encapsulation, a tablet for use as an inner core of a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, either tablets or capsules. Will be incorporated into Preferred coating materials include biodegradable, stepwise hydrolyzable, stepwise water-soluble and / or enzymatically degradable polymers and can be conventional "enteric" polymers. As will be appreciated by one of skill in the art, enteric polymers become soluble in the high pH environment of the lower digestive tract or are slowly degraded as the dosage form passes through the digestive tract, while enzyme degradable polymers are Especially in the colon, it is degraded by bacterial enzymes present in the lower digestive tract. Suitable coating materials for achieving delayed release include hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, Cellulosic polymers such as cellulose acetate trimellitate and sodium carboxymethyl cellulose; preferably acrylic acid polymers and copolymers formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate. , And EUDRAGIT®.L30D -55 and L100-55 (soluble at pH 5.5 or higher), EUDRAGIT (registered trademark). L-100 (soluble at pH 6.0 or higher), EUDRAGIT (registered trademark) .S (soluble at pH 7.0 or higher, high degree of esterification EUDRAGITS®. NE, RL and RS (water-insoluble polymers with varying degrees of permeability and expandability) such as EUDRAGIT® (Rohm Pharma; Westerstadt, Germany) Other methacrylic resins marketed in Japan; vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymers and ethylene-vinyl acetate copolymers; azo polymers, pectin, chitosan, amylose. And enzymatically degradable polymers such as guar gum; including but not limited to zein and shellac. There. Combinations of various coating materials may be used. Multilayer coatings using various polymers may be applied.

  The preferred coating weight of a particular coating material can be readily determined by one of ordinary skill in the art by evaluating the individual release profiles of tablets, beads and granules made with different amounts of various coating materials. It is a combination of substances, methods and application forms that yields the desired release profile, which can only be determined from clinical studies.

  The coating composition may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, glidants and the like. Plasticizers are usually present to reduce the brittleness of the coating and are generally about 10% to 50% by weight, based on the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethylacetyl citrate, castor oil and acetyl. Monoglyceride. Stabilizers are preferably used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce the effects of sticking during film formation and drying and are generally about 25% to 100% by weight of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearate can also be used. Pigments such as titanium dioxide can also be used. A small amount of antifoam agent, such as silicone (eg, simethicone), can also be added to the coating composition.

Manufacturing Methods As will be appreciated by those skilled in the art, there are many methods for manufacturing drug-containing tablets, beads, granules or particles that provide various drug release profiles, as described in the relevant texts and literature. It is available. Such methods include, but are not limited to, the following: Typically a polymeric material need not be incorporated, but the drug or drug-containing composition is coated with a suitable coating material. Increasing the drug particle size, placing the drug in a matrix, and forming a complex of the drug with a suitable complexing agent.

  Delayed release dosage units can be coated with a delayed release polymer coating using conventional techniques such as conventional coating pans, airless spray techniques, fluid bed coating equipment (with or without Wurster inserts). For more information on materials, equipment and methods for making tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al. Pharmaceutical. See Dosage Forms and Drug Delivery Systems, 6.sup.th Ed. (Media, PA: Williams & Wilkins, 1995).

  A preferred method for making sustained release tablets is by compressing a drug-containing mixture, such as a mixture of granules, made using a direct mixing, wet granulation or dry granulation process. Sustained-release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are preferably manufactured using compression rather than moulding. A preferred method for forming a sustained release drug-containing mixture is to provide the drug particles with one or more of diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. Direct mixing with excipients. Instead of direct mixing, the drug-containing mixture can be produced using wet granulation or dry granulation. Beads containing the active agent can also be prepared starting from any one of many conventional techniques, typically dispersions. For example, a typical method for producing drug-containing beads is a coating suspension or solution containing the active agent as a pharmaceutical excipient, such as polyvinylpyrrolidone, methylcellulose, talc, metal stearate, silicon dioxide, plasticizers. Dispersing or dissolving in Admixtures are used to coat bead cores such as sugar spheres (or so-called "nonpareils") having a size of about 60-20 mesh.

  Another procedure for making drug beads is to add one or more pharmaceutically acceptable excipients and drugs such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrants and the like. Mix, extrude the mixture, spheronize the extrudate, dry and optionally coat to form immediate release beads.

Five. Mucosal and pulmonary formulations
Dosage Actives and compositions thereof can be formulated for pulmonary or mucosal administration. Administration can include delivery of the composition to the lung, nose, mouth (sublingual, buccal), vaginal or rectal mucosa. In certain embodiments, the composition is formulated and delivered sublingually to a patient.

  In one embodiment, the compounds are formulated for pulmonary delivery such as intranasal administration or oral inhalation. The airways are the structures involved in the exchange of gas between air and blood flow. The lung is a branched structure that ends in the alveoli where gas exchange occurs. The alveolar surface area is the largest in the respiratory system and is where drug absorption occurs. The alveoli are covered with a thin epithelial or mucosal layer and secrete the surfactant phospholipids. The respiratory tract includes the lower respiratory tract, which includes the trachea following the upper respiratory tract, which includes the oropharynx and larynx, followed by a branch into the bronchi and bronchioles. The upper and lower respiratory tracts are called the conducting airways. The terminal bronchioles then divide into respiratory bronchi, leading to the final respiratory zone, the alveoli or deep lung. The deep lung or alveoli are the primary targets of inhaled therapeutic aerosols for systemic drug delivery.

  Pulmonary administration of therapeutic compositions containing low molecular weight drugs has been observed to be beta androgenic antagonists, for example for treating asthma. Other therapeutic agents that are active in the lung have been systemically administered and targeted via pulmonary absorption. Nasal delivery is considered a promising technique for the administration of therapeutic agents for the following reasons: The nose is available for drug absorption due to the coating of the epithelial surface with multiple microvilli. Has a large surface area; the epithelial layer is highly vascularized; venous blood from the nose passes directly through the systemic circulation, thus avoiding drug loss by first pass metabolism in the liver; Provides faster blood levels of therapeutic agent, faster onset of pharmacological activity, lower side effects, high total blood flow per cubic centimeter, porous endothelial basement membrane; and it is readily accessible Is.

  The term aerosol, as used herein, refers to any product of a fine mist of fine particles, whether solution or suspension, whether or not made with a propellant. Point to. Aerosols can be manufactured using standard techniques, such as sonication or high pressure treatment.

  Carriers for pulmonary formulations can be divided into carriers for dry powder formulations and carriers for administration as solutions. Aerosols for delivery of therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the formulation should be formulated as a solution, for example, buffered or unbuffered water or isotonic saline, or a suspension, for intranasal administration as drops or spray. You can Preferably, such solutions or suspensions are isotonic with nasal secretions and have about the same pH in the range of about pH 4.0 to about pH 7.4 or pH 6.0 to pH 7.0. . The buffer should be physiologically compatible, and merely by way of example, phosphate buffer. For example, a typical nasal decongestant is described as buffered at about pH 6.2. One of ordinary skill in the art can readily determine the appropriate saline content and pH of a non-toxic aqueous solution for nasal and / or upper respiratory administration.

  Preferably, the aqueous solution is water, a physiologically acceptable aqueous solution comprising a salt and / or buffer such as phosphate buffered saline (PBS), or any other acceptable for administration to an animal or human. It is an aqueous solution. Such solutions are well known to those of skill in the art and include, but are not limited to, distilled water, deionized water, pure or ultrapure water, saline, phosphate buffered saline (PBS). is not. Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may contain suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and tragacanth, and wetting agents such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoic acid.

  In another embodiment, solvents that are low toxicity organic (ie non-aqueous) Class 3 residual solvents such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether and propanol can be used in the formulation. The solvent is chosen based on its ability to readily aerosolize the formulation. The solvent must not deleteriously react with the compound. A suitable solvent should be used which either dissolves the compound or forms a suspension of the compound. The solvent must be sufficiently volatile to allow the formation of an aerosol of the solution or suspension. If desired, additional solvents or aerosolizing agents such as freon may be added to increase the volatility of the solution or suspension.

  In one embodiment, the composition can include minor amounts of polymers, surfactants, or other excipients well known to those of ordinary skill in the art. In this context, "small amount" means that there is no excipient that affects or mediates the uptake of the compound in the lung, and that the present excipient does not adversely affect the uptake of the compound in the lung. Means present in an amount.

  Dried lipid powder can be directly dispersed in ethanol due to its hydrophobicity. For lipids stored in an organic solvent such as chloroform, the desired amount of solution is placed in a vial and chloroform is evaporated under a stream of nitrogen to form a dry film on the surface of the glass vial. The film swells easily when reconstituted with ethanol. The suspension is sonicated in order to completely disperse the lipid molecules in the organic solvent. Non-aqueous suspensions of lipids can also be prepared in absolute ethanol using the reusable PARI LC Jet + nebulizer (PARI Respiratory Equipment, Monterrey, CA).

  Dry powder formulations (DPF) with large particle size have improved flowability properties such as less aggregation, easier aerosolization, and potentially less phagocytosis. Dry powder aerosols for inhalation therapy are generally prepared with a mean range of aerodynamic diameters of 1 to 10 microns, but predominantly in the range of less than 5 microns. Among other possible benefits, large "carrier" particles (drug-free) have been delivered with therapeutic aerosols to help achieve efficient aerosolization.

  Producing polymer particles using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, and other methods well known to those skilled in the art. You can The particles can be made using methods known in the art for making microspheres or microcapsules. A preferred method of manufacture is by spray drying and lyophilization using a solution containing a surfactant, spraying to form droplets of the desired size, and removing the solvent.

  The particles can be manufactured with suitable materials, surface roughness, diameter and tap density for localized delivery to selected areas of the respiratory tract, such as the deep lung or upper respiratory tract. For example, denser or larger particles can be used for upper respiratory delivery. Similarly, a mixture of different sized particles with the same or different active agents can be administered to target different regions of the lung in a single dose.

6. Topical and transdermal formulations Transdermal formulations can also be prepared. These are typically gels, ointments, lotions, sprays or patches, all of which can be manufactured using standard techniques. Transdermal formulations can include penetration enhancers.

  A "gel" is a colloid in which the dispersed phase combines with the continuous phase to produce a semisolid material such as jelly.

  An "oil" is a composition containing at least 95% by weight of lipophilic substances. Examples of lipophilic substances include, but are not limited to, natural and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof.

  The “continuous phase” means a liquid in which a solid is suspended or a liquid in which droplets of another liquid are dispersed, and is sometimes called an external phase. This also means the colloidal fluid phase in which the solid or fluid particles are distributed. When the continuous phase is water (or other hydrophilic solvent), the water-soluble or hydrophilic drug is dissolved (rather than dispersed) in the continuous phase. In multi-phase formulations (eg emulsions), the separate phases are suspended or dispersed in the continuous phase.

  An "emulsion" is a composition that comprises a mixture of immiscible components that are uniformly mixed. In certain embodiments, immiscible components include lipophilic and aqueous components. An emulsion is a liquid preparation that is distributed in small globules over a body of a second liquid. The dispersion is a discontinuous phase and the dispersion medium is a continuous phase. When the oil is a dispersion and the aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, while when the water or aqueous solution is the dispersed phase and the oil or oily substance is the continuous phase, a water-in-oil type Known as an emulsion. Either or both of the oil and water phases may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers and other excipients. Preferred excipients include surfactants, especially nonionic surfactants; emulsifiers, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, especially glycols such as propylene glycol. The oily phase may contain other oily pharmaceutically approved excipients. For example, substances such as hydroxylated castor oil or sesame oil can be used in the oil phase as surfactants or emulsifiers.

"Emollient" is a topical agent to the skin soften or smooth, are generally known in the art, "Handbook of Pharmaceutical Excipients", 4 ^th Ed., In the Compendium, such as Pharmaceutical Press, 2003 Have been described. These include, but are not limited to, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl ester wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, Glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light oil, medium chain triglyceride, mineral oil and lanolin alcohol, petrolatum, petrolatum and lanolin alcohol, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and them. Including the combination of. In one embodiment, the emollient is ethylhexyl stearate and ethylhexyl palmitate.

  A "surfactant" is a surfactant that enhances the emulsification, foaming, dispersion and wetting properties of a product by reducing the surface tension. Suitable nonionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polysorbate, sorbitan ester, benzyl alcohol, benzyl benzoic acid, cyclodextrin, glyceryl monostearate. , Poloxamer, povidone and combinations thereof. In one embodiment, the nonionic surfactant is stearyl alcohol.

  An "emulsifier" is a surface-active substance that suspends one liquid in another and promotes the formation of a stable mixture of oil and water or emulsion. Common emulsifiers are metal soaps, certain animal and vegetable oils, and various polar compounds. Examples of suitable emulsifiers are gum arabic, anionic emulsifying wax, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glyceryl monostearate, glyceryl monooleate, hydroxypropyl. Cellulose, hypromellose, lanolin, hydrous, lanolin alcohol, lecithin, medium chain triglyceride, methyl cellulose, mineral oil and lanolin alcohol, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamer, poly Oxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, starch Polyoxyethylene phosphate, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dihydrate, sodium lauryl sulfate, sorbitan ester, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof. Is mentioned. In one embodiment, the emulsifier is glycerol stearate.

  A "lotion" is a low to medium viscosity liquid formulation. Lotions may contain a finely divided powder which is soluble in the dispersion medium through the use of suspending and dispersing agents. Alternatively, the lotion may have a liquid material immiscible with the vehicle as the dispersed phase, usually dispersed with an emulsifying agent or other suitable stabilizing agent. In one embodiment, the lotion is in the form of an emulsion having a viscosity of 100-1000 centistokes. The fluidity of the lotion allows for rapid and uniform application over a large surface area. Lotions are typically intended to dry on the skin, leaving a thin coat of the pharmaceutical ingredient on the surface of the skin.

  A "cream" is a viscous liquid or semi-solid emulsion, either "oil-in-water" or "water-in-oil". The cream may contain emulsifiers and / or other stabilizers. In one embodiment, the formulation is in the form of a cream having a viscosity of 1000 centistokes or higher, typically in the range of 20,000-50,000 centistokes. Creams are often preferred over ointments as they are generally easier to spread and easier to remove.

  An emulsion is a liquid preparation that is distributed in small globules over a body of a second liquid. The dispersion is a discontinuous phase and the dispersion medium is a continuous phase. When the oil is a dispersion and the aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, while when the water or aqueous solution is the dispersed phase and the oil or oily substance is the continuous phase, it is water-in-oil. Known as type emulsion. The oil phase may be composed of at least a portion of a propellant such as an HFA propellant. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially nonionic surfactants; emulsifiers, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, especially glycols such as propylene glycol. The oily phase may contain other oily pharmaceutically approved excipients. For example, substances such as hydroxylated castor oil or sesame oil can be used in the oil phase as surfactants or emulsifiers.

  A subset of emulsions are self-emulsifying systems. These drug delivery systems are typically capsules (hard or soft shell) consisting of the drug dispersed or dissolved in a mixture of a surfactant and a lipophilic liquid, such as an oil or other water immiscible liquid. is there. When the capsule is exposed to the aqueous environment and the outer gelatin shell dissolves, the contact between the aqueous medium and the capsule contents instantly produces very small emulsion droplets. These are typically within the size range of micelles or nanoparticles. No mixing force is required to form an emulsion, as is typically the case for emulsion formulation processes.

  The basic difference between creams and lotions is the viscosity, which is dependent on the amount / use of various oils used to prepare the formulation and the proportion of water. Creams are generally thicker than lotions and have a variety of uses, often with a wider variety of oils / butters depending on the desired effect on the skin. In cream formulations, the proportion of water base is about 60-75%, the oil base is about 20-30% of the total, 100% in total with other percentages which are emulsifiers, preservatives and additives. Is.

  An "ointment" is a semisolid formulation containing an ointment base and optionally one or more active agents. Examples of suitable ointment bases are hydrocarbons (eg petrolatum, white petrolatum, yellow ointments, and mineral oils); absorbent bases (hydrophilic petrolatum, anhydrous lanolin, lanolin and cold creams); water removable groups. Agents (eg hydrophilic ointments); and water-soluble bases (eg polyethylene glycol ointments). Pastes typically differ from ointments in that they have a higher percentage of solids. Pastes are typically more absorbent and less greasy than ointments prepared with the same ingredients.

  A "gel" is a semi-solid system containing a dispersion of small or large molecules in a liquid vehicle that becomes semi-solid by the action of a thickener or polymeric material dissolved or suspended in the liquid vehicle. The liquid can include lipophilic components, aqueous components, or both. Some emulsions may be gels, and may otherwise include gel components. However, some gels are not emulsions because they do not contain a homogeneous mixture of immiscible components.

Suitable gelling agents include, but are not limited to, modified celluloses such as hydroxypropyl cellulose and hydroxyethyl cellulose; carbopol homopolymers and copolymers; and combinations thereof. Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alkylene glycols such as propylene glycol; dimethyl isosorbide; alcohols such as isopropyl alcohol and ethanol. Solvents are typically chosen for their ability to dissolve the drug. Other additives that improve the skin feel and / or emollient properties of the formulation may also be incorporated.
Examples of such additives include isopropyl myristate, ethyl acetate, C12-C15 alkylbenzoates, mineral oil, squalane, cyclomethicone, capric / caprylic triglycerides, and combinations thereof. It is not limited.

  The foam consists of an emulsion combined with a gaseous propellant. Gaseous propellants consist primarily of hydrofluoroalkanes (HFA). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227). Mixtures and blends of these with other HFAs, which are currently approved or may be approved for medical use, are suitable. It is preferred that the propellant is not a hydrocarbon propellant that can generate flammable or explosive vapors during spraying. In addition, it is preferred that the composition be free of volatile alcohols that may generate flammable or explosive vapors during use.

  Buffers are used to control the pH of the composition. It is preferred that the buffer buffer the composition to a pH of about 4 to about pH 7.5, more preferably about pH 4 to about pH 7, most preferably about pH 5 to about pH 7. In a preferred embodiment, the buffer is triethanolamine.

  Preservatives can be used to prevent fungal and microbial growth. Suitable antifungal and antibacterial agents include benzoic acid, butylparaben, ethylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenyl ale. Examples thereof include alcohol and thimerosal, but are not limited thereto.

Additional agents that may be added to the formulation include penetration enhancers. In some embodiments, the penetration enhancer increases the solubility of the drug, improves transdermal delivery of the drug, particularly across the stratum corneum and across the skin, or a combination thereof. Some penetration enhancers cause skin irritation, skin toxicity and dermal allergy. However, as more commonly used, urea, (carbonyldiamide), imidourea, N, N-diethylformamide, N-methyl-2-pyrrolidone, 1-dodecaazacycloheptan-2-one, thioglycol Oleic acid and its ester derivatives such as calcium acid salt, 2-pyrrolidone, N, N-diethyl-m-toluamide, methyl, ethyl, propyl, isopropyl, butyl, vinyl, glyceryl monooleate, sorbitan monolaurate and sorbitan monooleate Other fatty acid esters such as sorbitan ester, isopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleate, and
BRIJ (registered trademark) 76 (stearyl poly (10 oxyethylene ether), BRIJ (registered trademark) 78 (stearyl poly (20) oxyeletin ether), BRIJ (registered trademark) 96 (oleyl poly (10) oxyethylene ether) and BRIJ® 721 (stearyl poly (21) oxyethylene ether) (ICI Americas Inc. Corp.). Methods for enhancing chemical penetration and transdermal drug delivery are described in Inayatra et al., Tropical Journal of Pharmaceutical Research, 8 (2): 173-179 (2009) and Fox et al., Molecules, 16: 10507-10540 (2011) .In some embodiments, the penetration enhancer is an alcohol, such as ethanol, or a book. Disclosed or encompassed by the specification or otherwise known in the art.

  Delivery of drugs by the transdermal route has been known for many years. The advantages of transdermal drug delivery compared to other types of drug delivery such as oral, intravenous and intramuscular include the avoidance of hepatic first pass metabolism, the ability to discontinue system elimination and the usual gastrointestinal tract of oral dosage forms. It includes the ability to control drug delivery for longer than transit and the ability to change the properties of biological barriers to absorption.

  The effectiveness of controlled release transdermal devices generally depends on the delivery of a known flux of drug to the skin over an extended period of days, days, or weeks. Two mechanisms are used to regulate drug flux: the drug is contained within a drug reservoir that is separated from the wearer's skin by a synthetic membrane through which the drug diffuses; It is retained in solution or suspension within a polymer matrix through which it diffuses into the skin. Devices incorporating a reservoir deliver a stable drug flux across the membrane as long as excess undissolved drug remains in the reservoir; a matrix or monolithic device typically provides a matrix close to the skin. It is characterized by a decrease in drug flux over time as the layer runs out of drug. Reservoir patches typically include a porous membrane that covers a reservoir of a drug with controlled release, which allows a thin layer of drug embedded in a polymer matrix (e.g., an adhesive layer) to be melted while heat-matrixing the matrix or monolithic layer. The release of drug from the device can be controlled. Thus, the active agent may be released from the patch in a controlled manner, not necessarily a controlled release formulation.

  A patch protects the patch during storage and is removed prior to use; a drug or drug solution that is in direct contact with a release liner; an adhesive that acts to adhere the patch to the skin and the components of the patch; One or more membranes that can separate the layers of the and control the release of the drug from reservoirs and multilayer patches and the like; and a backing that protects the patch from the external environment.

  As a common type of transdermal patch, along with the entire system for the skin, an adhesive layer contains the drug and serves to adhere the various layers of the patch together, but is also responsible for the release of the drug. Layered drug-soluble adhesive patch; similar to a single layer drug-soluble adhesive patch, but with, for example, one layer for immediate release of the drug and another for controlled release of the drug from the reservoir Multi-layered drug-soluble adhesive patch containing multiple layers, such as one layer; Reservoir patch characterized in that the drug layer is a liquid compartment containing a drug solution or suspension separated by an adhesive layer; Drug solution Or a matrix patch in which a drug layer of a semi-solid matrix containing a suspension is surrounded by said adhesive layer and partially covered by an adhesive layer; and the adhesive layer brings together the various layers Contact Not only it helps to, but also include vapor patch, wherein that release vapors, but is not limited thereto. Methods for making transdermal patches are disclosed in US Pat. Nos. 6,461,644, 6,676,961, 5,985,311, and 5,948,433.

  In a particularly preferred embodiment, THIP or a derivative thereof is formulated for transdermal delivery and is administered using a transdermal patch. In some embodiments, the formulations, patches, or both are designed for sustained release of THIP or its derivatives. Exemplary symptoms, pharmacological and physiological effects are discussed in more detail below.

III. Methods of Treating Secondary Insomnia Provided are methods of treating secondary insomnia. Methods reduce sleep disruption, increase slow wave sleep (SWS) and / or slow wave activity (SWA), normalize sleep architecture, reduce secondary insomnia, increase non-REM (NREM) sleep , Increase sleep continuity, enhance Delta activity in NREM, increase or improve total sleep time (TST), improve or improve sleep efficiency, decrease total wake time (TAA), wake frequency (NWA), shortened continuous sleep latency (LPS), decreased post-sleep wakefulness (WASO), or any combination thereof, in an effective amount of 4,5,6, It may include administering to the patient 7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP) or a derivative thereof. In a preferred embodiment, REM sleep is not substantially reduced. In some embodiments, the method is effective in reducing, delaying, or preventing one or more other clinical symptoms of a neurodegenerative disease or central nervous system disease or disorder.

A. Treatment protocol
It has been discovered that THIP and its derivatives can be used to treat secondary insomnia. Secondary insomnia is another problematic condition or side effect, such as emotional, neurological or other medical or sleep disorders. Therefore, the patient to be treated typically suffers from both insomnia and the underlying disease, disorder or condition that causes insomnia.

  Emotional disorders that cause insomnia include depression, anxiety and post-traumatic stress disorder. Conditions that cause chronic pain such as arthritis and headache; dyspnea conditions such as asthma and heart failure; overactive thyroid gland; gastrointestinal disorders such as heartburn; stroke; sleep disorders such as restless legs and sleep-related respiratory disorders; menopause and hot flashes Medications, for example asthma drugs such as theophylline, and some allergic and cold drugs, beta blockers and drugs used to treat heart disease can cause secondary insomnia. The use of caffeine and other stimulants, tobacco and other nicotine products, alcohol and other sedatives can result in secondary insomnia.

  In a preferred embodiment, secondary insomnia is caused by a neurological disease or disorder as described in more detail below.

1. Sleep Structures In some embodiments, the patient has or is at risk of developing slow wave sleep, disruption of sleep architecture, or benefits from increased slow wave sleep. Thus, in some embodiments, the composition is administered in an amount effective to reduce, alleviate, or prevent one or more sleep-related symptoms. In a preferred embodiment, THIP or a derivative thereof reduces sleep interruption, increases slow wave sleep (SWS) and / or slow wave activity (SWA), normalizes sleep architecture and reduces secondary insomnia. , Increase non-REM (NREM) sleep, enhance sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), improve or improve sleep efficiency, total wake time ( Effective for decreasing TAA), decreasing number of wakefulness (NWA), shortening continuous sleep latency (LPS), decreasing waking after sleep onset (WASO), or any combination thereof. Administered to the patient in an amount. In a preferred embodiment, REM sleep is not substantially reduced.

Sleep is an active process produced and regulated by a complex set of nervous systems located primarily in the hypothalamus, brainstem, and thalamus. Sleep is altered in many neurological disorders by mechanisms such as lesions in the brain regions that control sleep and wakefulness, lesions or diseases that cause pain, loss of movement and treatment. Nocturnal behavioral phenomena such as excessive daytime sleepiness (EDS), sleep fragmentation, insomnia, sleep-disordered breathing (SDB), rapid eye movement (REM) sleep behavior disorders or nighttime seizures, restless leg syndrome, and cycles Sexual Limb Movement Disorder (PLMS) is a common symptom and finding in neurological disorders (Jennum et al., Chapter 39: Sleep disorders in neurodegenerative disorders and stroke, European Handbook of Neurological Management , Volume 1, 2nd Edition (Ed . Gilhus et al.) Blackwell Publishing Ltd. 2011). In some cases, sleep disorders have a predominant effect on the disease course in neurological disorders, particularly those associated with daytime functioning, quality of life, morbidity and mortality.

  Evidence has also emerged that patients with Huntington's disease (HD) may suffer abnormalities in control of both sleep and daily or "circadian" rhythms (Morton, "HDBuzz Special Feature: Huntington's disease and sleep. HDbuzz.net/115, (ed., Wild), February 06, 2013). Therefore, sleep and circadian dysfunction are symptoms of HD. Other sleep-related symptoms in patients with Huntington's disease in reduced involuntary movements: disturbed sleep patterns with increased sleep latency, decreased sleep efficiency, frequent nighttime awakening, and longer duration with less slow-wave sleep Sleep disorders, such as waking hours, tend to decrease during sleep. These abnormalities may be partially correlated with the duration of the disease, the severity of clinical symptoms, and the degree of caudate atrophy. The sleep phenotype of Huntington's disease may also include insomnia, a progressive sleep phase, rhythmic leg movements, REM sleep behavior disorder (RBD) and reduced REM sleep. Reduced REM sleep occurs before chorea, and mutant Huntington's can affect REM sleep and motor control during sleep.

  Sleep-wake problems, often unrecognized, are frequent and a complication of amyotrophic lateral sclerosis (ALS). Sleep disorders such as insomnia, sleep-disordered breathing and restless legs syndrome have been reported in all ALS patients, despite a limited number of studies and a small population studied to date (Lo Coco et al., Neurodegenerative Disease Management, 2 (3): 315-324 (2012)). The prognosis of ALS is closely related to respiratory muscle strength, with frequent nocturnal sudden death during sleep. Respiratory indicators such as low nocturnal oxygen saturation are associated with poor prognosis. REM sleep may be significantly reduced in patients with diaphragm involvement. Patients with dementia often present with circadian disorders being treated with melatonin and phototherapy.

  Sleep and circadian dysfunction may be caused by other symptoms of neurodegenerative disease or by factors independent of disease. Sleep and circadian dysfunction are personal habits, such as getting too late, getting up early, taking drugs that interfere with sleep, and / or causing late night activities such as work, or excessive irritation by television, etc. , Can be caused by lifestyle or environment. Sleep and circadian disorders in patients with neurological disorders may contribute to symptoms of illness that are exacerbated by sleep deprivation, such as wakefulness and anxiety, and are involved in daytime function, quality of life, morbidity, and mortality It may affect the course of the disease in advance. For example, sleep disorders have been reported to progressively worsen with disease progression in ALS, indicating a relationship between disease severity and neurodegenerative processes. In addition, patients with neurodegenerative diseases may not have the same neuroprotection that healthy individuals rely on to address sleep deprivation.

  Sleep deprivation can be the result of several disorders such as anxiety, depression, pain, choking, salivation, fasciculations, cramps, nocturia, getting comfortable in bed, and being unable to move freely. is there. Sleep disorders can bring many reflections to the patient, such as excessive daytime somnolence, fatigue, cognitive impairment, poor quality of life and poor survival. (Lo Coco et al., Neurodegenerative Disease Management, 2 (3): 315-324 (2012)).

  Circadian rhythm and sleep are often used interchangeably, but these terms are two different processes. Circadian rhythms are biological processes that change approximately every 24 hours. They are regulated by a small part of the brain called the suprachiasmatic nucleus or SCN, which regulates physical activity such as when to wake up and when to sleep. Although sleep is a circadian behavior, it is only one of many circadian behaviors affected by SCN. Others include heart rate, hormone secretion, blood pressure and body temperature.

At night, they follow a predictable pattern that cycles between deep restorative sleep (deep sleep) and more sensitive stages (collectively referred to as non-REM or NREM) and dreaming (REM sleep). Specifically, the sleep cycle includes stages W (wakefulness), N1 (NREM1), N2 (NREM2), N3 (NREM3) and R (REM). Sleep stages can be identified by monitoring a patient's brain electrical activity (eg, electroencephalogram).
See Iber et al., `` The AASM Manual for the Scoring of Sleep and Associated Events, American Academy of Sleep Medicine, '' pg, for determining the criteria for each stage and how to determine the stage of the sleeping patient and how to profile the patient's sleep architecture. 1-57 (2007), which is incorporated herein by reference in its entirety.

  The stages of REM sleep and NREM sleep together form a complete sleep cycle. Each cycle typically lasts about 90 minutes and is repeated 4-6 times during the course of a typical night sleep. A normal adult spends about 50% of his total sleep time in stage 2 sleep, 20% in REM sleep, and 30% in the rest, including deep sleep. For example, a typical first sleep cycle N1 features a mixed voltage pattern of low voltage and may last from about 1 to about 10 minutes. The upcoming second stage N2 is characterized by sleep spindles and / or K complex waves in the electroencephalography. N2 generally lasts from about 10 to about 25 minutes. As N2 sleep progresses, the characteristic high-voltage slow-wave activity of N3, the third stage of NREM sleep, gradually emerges. This phase, which generally lasts about 20-40 minutes, is called "slow wave", "delta" or "deep" sleep. Following the N3 phase of sleep, a series of physical exercises usually herald an "elevation" to a light NREM sleep phase. Typically, a 5-10 minute period of N2 precedes the first REM sleep episode. REM sleep episodes can last only 1-5 minutes initially, but generally become longer at night. During a typical night, N3 sleeps occupy less time than the first sleep than the second sleep and may disappear entirely from later cycles. The average length of the first NREM-REM sleep cycle is 70-100 minutes and the average length of the second and subsequent cycles is about 90-120 minutes. REM sleep accounts for approximately 20-25% of total sleep in a typical healthy adult ("Natural Patterns of Sleep" healthysleep.med.harvard.edu/healthy/science/what/sleep-patterns-rem-nrem, A resource from the Division of Sleep Medicine at Harvard Medical School (2007)).

  The duration of the stages of the sleep cycle alone or in combination with the circulation of the stages can be referred to as the sleep architecture of the subject. In some embodiments, the neurodegenerative disease patient has an interrupted sleep architecture, eg, a change in the duration of one or more sleep cycles, a change in the duration or number of sleep cycles, as compared to a control or baseline. , Or any combination thereof. The control value or reference value in this case is, for example, the average normal duration of the stages, or the average normal duration or the number of cycles in subjects who do not suffer from interrupted or disturbed sleep construction (e.g., healthy subjects). possible.

  Thus, in some embodiments, THIP or a derivative thereof is effective to normalize a patient's sleep architecture, for example by bringing one or more aspects of the patient's sleep architecture closer to a sequence of sleep architecture in a normal subject. Dose.

Slow Wave Sleep (SWS), often referred to as deep sleep, consists of N3 NREM sleep. The 1968 classification that combined sleep stages 3-4 was reclassified in 2007 as stage N3. The period consisting of more than 20% of slow wave (delta) sleep (30 seconds of sleep) is now considered to be stage 3 (Gazzaniga, Just the Facts 101, e-Study Guide for: Psychological Science , Content Technologies. Inc., 2014). Slow wave sleep is thought to be important in organizing new memories, and in sleep deprivation studies in humans, among other things, the important function of slow wave sleep could enable recovery from daily brain activity. Has been shown to be.

  Rapid eye movement (REM) sleep is a stage of sleep characterized by rapid, random movements of the eye and can be divided into two categories: tonicity and phasic. Criteria for REM sleep include rapid eye movements, low muscle tone, and rapid, low-voltage EEG, features that can be identified on polysomnography. REM sleep typically accounts for about 90-120 minutes of night sleep, or 20-25% of total sleep.

  THIP or a derivative thereof or a combination thereof is administered to a subject in an effective amount to increase the length of one or more N3 stages in a patient's sleep, increasing the number of N3 stages in the patient's sleep . In some embodiments, the composition is for at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, or at least 120 minutes over a sleep period (e.g., overnight). , Increase slow wave sleep. In some embodiments, the composition more than doubles the amount of slow wave sleep in the patient.

2. Dosage and Administration The disclosed method of treating secondary insomnia typically comprises administering to a patient in need thereof an effective amount of THIP or a derivative thereof, preferably above It is a medically acceptable composition discussed in detail.

  An effective or therapeutically effective amount typically reduces sleep disruption, increases slow wave sleep (SWS) and / or slow wave activity (SWA), normalizes sleep architecture, and reduces secondary insomnia. , Increase non-REM (NREM) sleep, increase sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), improve or improve sleep efficiency, total wake time Sufficient for reducing (TAA), decreasing number of wakefulness (NWA), shortening continuous sleep latency (LPS), decreasing waking after sleep onset (WASO), or any combination thereof Dose. In a preferred embodiment, REM sleep is not substantially reduced.

  In some embodiments, the method reduces or prevents one or more neuropsychiatric morbidity in a patient having a neurodegenerative disease or disorder. Thus, the amount is effective to treat or prevent one or more symptoms of a neurodegenerative disease or central nervous system disorder, or otherwise provide a desired pharmacological and / or physiological effect. sell.

  The exact dosage depends on various factors such as patient-dependent variables (eg age, immune system health, clinical symptoms, etc.). Exemplary dosages, symptoms, pharmacological and physiological effects are discussed in more detail below.

  Studies on the effect of gaboxadol on improving sleep in subjects have been performed by Walsh et al., Journal of Clinical Sleep Medicine, 5 (2): S27-S32 (2009) and Deacon et al., Sleep, 30 (3): 281-287 (2007). ,) And reviewed. For example, 15 mg gaboxadol resulted in significantly more stage 4 sleep and SWS (although not stage 3) compared to placebo in sleep-restricted subjects (gaboxadol averaged compared to placebo). SWS of 21.8 minutes or longer was seen over four sleep-restricted nights (both p <0.001), Walsh et al., Journal of Clinical Sleep Medicine, 5 (2): S27-S32 (2009). Gaboxadol also resulted in a small but significant reduction in stage 1 sleep, REM sleep, and awakening or transition to stage 1 sleep compared to placebo.

  In another dose-response study, 109 healthy individuals with transient sleep disturbances due to 4 hours of habitual sleep were given 5, 10 or 15 mg gaboxadol (Walsh et al., Sleep, 30: 593-602 (Walsh et al., Sleep. 2007)). The study results show that gaboxadol caused a dose-related increase in SWS of about 5 to 22 minutes compared to placebo. At all doses, TST increased significantly for approximately 30 minutes (p <0.001) and WASO decreased for approximately 17-20 minutes (p <0.05) compared to placebo. Gaboxadol also improved a subjective measure of sleep quality when compared to placebo.

  A dose-related study of 40 patients with primary insomnia who received 10 and 20 mg gaboxadol also reported an increase in SWS compared to placebo (10 mg: p <0.01; 20 mg: p <0.001). Lundahl et al., Psychopharmacology (Berl) 195: 139-46 (2007) Gaboxadol significantly reduced WASO at a dose of 20 mg (p <0.01), and gaboxadol significantly reduced NASO at both doses. Gaboxadol significantly increased TST even at a dose of 20 mg (p <0.05).

  Another study of the effect of gaboxadol on primary insomnia in 26 people showed that a dose of 15 mg enhances SWS without significantly affecting stage 1, stage 2, or REM sleep. (Deacon et al., Sleep, 30 (3): 281-287 (2007)). Gaboxadol at the 5 mg and 15 mg doses significantly improved TST (p <0.05). The results also show improved WASO, but statistical significance was achieved only at the 5 mg dose. The sustained sleep latency was significantly reduced even at a dose of 15 mg gaboxadol (p <0.05).

  Furthermore, in preclinical studies and in healthy young and elderly studies, gaboxadol increased NREM sleep, increased sleep duration, enhanced Delta activity during NREM sleep, and did not suppress REM sleep. It was found to increase SWS / SWA (Lancel et al., Neuroreport, 7: 2241-5 (1996), Lancel et al., Sleep, 20: 1099-104 (1997), Faulhaber et al., Psychopharmacology (Berl), 130 :. 285-91 (1997), Lancel, Sleep, 22: 33-42 (1999), Lancel et al., Am J Physiol Endocrinol Metab, 281: E130-7 (2001), Mathias et al., Psychopharmacology (Berl), 157: 299. -304 (2001), Mathias et al., Neuropsychopharmacology, 30: 833-41 (2005)).

  In a preferred embodiment, THIP or a derivative thereof is administered to a patient in an amount effective to increase slow wave sleep in the patient.

  Particularly preferred embodiments include formulations for sustained release. For example, the formulation may be suitable for administration once daily or less. In some embodiments, the composition is administered to the patient only once every 24-48 hours. In some embodiments, THIP or a derivative thereof is administered the night before sleep. In other embodiments, THIP or a derivative thereof is administered in the morning or at least hours before sleep.

  The timing of administration of the composition depends on the formulation used and / or the route of administration. In some embodiments, administration of the composition is given as a long-term treatment regimen in which a pharmacokinetic steady state is achieved. Dosage for oral or parenteral administration may be administered directly in relation to the particular sleep period, for example 10 minutes to 3 hours before the onset of sleep. Thus, the composition may be administered directly in relation to a particular sleep period, for example 5 minutes to 5 hours before the onset of sleep, 10 minutes to 3 hours before the onset of sleep.

  The preferred route of administration is transdermal, for example a transdermal patch or gel that contacts the skin of the patient. In certain embodiments, transdermal formulations are administered to a patient using a transdermal patch before the patient sleeps (eg, at night). In another particular embodiment, the transdermal formulation is administered to the patient in the morning using a transdermal patch. As described in further detail below, in some methods, in patients with a neurodegenerative disease or central nervous system disorder, an amount of THIP or a THP amount effective to reduce sleep disorders or slow-wave sleep in the patient is reduced. The derivative is administered transdermally.

  Generally, by way of example, dosage forms useful in the disclosed methods are specific examples of preferred doses: 0.1-1,000 mg, 1-200 mg, 5-175 mg, 7.5-150 mg, or Dose in the range 10-125 mg, or 12.5-150 mg, or 15-125 mg, or 17.5-100 mg, or 20-75 mg, or 22.5-60 mg, or 25-50 mg, and 1 mg, 5 It may include doses of mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, and 100 mg. Typically, such doses are administered to humans once, twice, or three times daily, or every other day.

  A typical oral dosage form preferably contains from about 2.5 mg to about 30 mg THIP. Preferably, THIP is in crystalline form. Further embodiments of the medicament include 2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg. , 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg, for example, an effective amount of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg. Including THIP. An exemplary embodiment is about 5 mg to about 20 mg of crystalline THIP, such as the hydrochloride salt of THIP. Typically, such doses are administered to humans once, twice, or three times daily, or every other day. In some embodiments, the total amount administered to a patient in 24 hours is 1 mg to 50 mg. In some embodiments, the patient is started at a low dose and the escalated dose of the drug is well tolerated by the patient.

When administered orally to healthy subjects, gaboxadol is rapidly absorbed (tmax of 30-60 minutes) and eliminated (t _{1/2 of} 1.5 hours) (Deacon et al., Sleep, 30 (3): 281-287). (2007)). Greater than 95% of the dose is excreted in urine, remains almost unchanged, and the only metabolite formed in significant amounts is the glucuronide conjugate.

  In some embodiments, the effect of the composition on the patient is compared to a control. For example, the effect of the composition on a particular condition, pharmacological or physiological index can be compared to the condition of an untreated patient or a patient prior to treatment. In some embodiments, the symptom, pharmacological or physiological index is measured in the patient prior to treatment and one or more times after initiation of treatment. In some embodiments, the control is determined based on measuring a symptom, pharmacological or physiological index in one or more subjects (e.g., healthy subjects) who do not have the disease or condition being treated. Reference level or average. In some embodiments, the effects of treatment are compared to conventional treatments known in the art, such as one of those discussed herein.

3. Intravenous Delivery In some embodiments, the composition is administered by intravenous injection or infusion. When administered orally, the transport of gaboxadol from the intestine to the portal circulation is via the transporter PAT1. Since the amino acid substrates of the PAT1 transporter, including but not limited to proline, tryptophan, alanine, and glycine, are present in food, their presence during oral administration affects the absorption of gaboxadol. Can affect. More specifically, PAT1 inhibitors such as L-tryptophan can decrease the absorption rate constants k _a and C _max of gaboxadol and increase T _max (eg, Larsen et al., Br. J. Pharmacol., 157). (8): 1380-1389 (2009) and WO 2009/056146). It is therefore believed that intravenous administration may improve control of plasma (and brain levels) over oral administration due to the significant variation in gaboxadol intake by the oral route. Furthermore, high peak concentrations of gaboxadol in predisposed individuals cause hallucinations, leading to discontinuation of drug administration in some patients. Intravenous delivery provides the ability to titrate the dose ensuring that high peak Cmax is not observed, helping to avoid this potential adverse event.

  In some embodiments, the use of intravenous administration allows the composition to be delivered at a lower dose than if delivered, for example, orally. The preferred rate for IV delivery is 0.001 mg / kg / hour to 1 mg / kg / hour. Treatment can be administered over the course of minutes, hours, or days. Dosages, such as the overall daily dose, are discussed above. In certain embodiments, one treatment comprises intravenously administering from about 0.001 mg to about 30 mg THIP or a derivative thereof to a patient in need thereof. In some embodiments, the administration is repeated at least once at intervals of about 3 to about 5 hours. In some embodiments, the administration is repeated at least 6 times during the 24 hour period. In various embodiments, the administration is repeated 3-8 times (e.g., 3, 4, 5, 6, 7, or 8 times) during a 24-hour period, from about 0.001 mg to about 30 mg. THIP or a derivative thereof is delivered over 24 hours. Dosage regimens are also discussed above. For example, in some embodiments, one treatment can be repeated at intervals of 1, 2, 3, 4, 5, 6, 7 or more days, weeks, or months. Intravenous administration is easy to monitor for side effects associated with dose escalation, improves the ability to control plasma levels, and includes the ability to titrate the dose. Thus, in some embodiments, the intravenous dosing regimen provides a dose of THI or a derivative thereof within 24 hours until the dose is effective to treat the patient, preferably without inducing undesirable side effects. Including titration from 0.001 mg to about 30 mg. Intravenous protocols can also be adapted from those known in the art. See, for example, US Application Publication No. 2009/0143474.

B. Conditions, Symptoms, Patients and Diseases Treated The disclosed compositions are typically administered to patients with neurodegenerative diseases or disorders or central nervous system disorders, particularly those that result in secondary insomnia in the patient. . Neurodegeneration refers to the progressive loss of neuronal structure or function, such as neuronal death. Exemplary diseases and disorders are shown below. In some embodiments, the composition is administered to a patient who does not have a neurodegenerative disease or disorder.

  Neurodegeneration and its diseases and disorders include genetic mutations or mutations; protein misfolding; intracellular mechanisms such as dysregulated proteolytic pathways, membrane damage, mitochondrial dysfunction, or defects in axonal transport; apoptosis, autophagy. Effects, defects in programmed cell death mechanisms such as cytoplasmic cell death; and combinations thereof. More specific mechanisms common to neurodegenerative disorders include, for example, oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and / or protein aggregation.

1. Symptoms In some embodiments, the disclosed compositions are provided in an amount effective to reduce or prevent one or more molecules or clinical symptoms of a neurodegenerative disease, or one or more mechanisms that cause neurodegeneration. Is administered to a patient in need thereof. Symptoms of neurodegenerative diseases are known in the art and will vary from disease to disease. In some embodiments, the disease exhibits or is characterized by one or any combination of the following symptoms or diseases: stress, anxiety, seasonal depression, insomnia and fatigue, schizophrenia. , Panic attacks, depression, dysfunction in regulation of appetite, insomnia, psychotic disorders, epilepsy, senile dementia, various disorders due to normal or pathological aging, migraine, memory loss, cerebral circulation disorders, Cardiovascular conditions, digestive system conditions, fatigue due to anorexia, obesity, pain, psychotic disorders, diabetes, senile dementia, or sexual dysfunction. In some embodiments, the patient does not exhibit one or more of the above symptoms.

  In some embodiments, the patient is medically diagnosed as having a neuroprotective condition by exhibiting clinical (eg, physical) symptoms of the disease. As mentioned above, in some patients the emergence of sleep-related disorders precedes the clinical diagnosis of the disease. Thus, in some embodiments, the compounds or compositions disclosed herein are administered prior to clinical diagnosis of the disease or condition. In some embodiments, genetic testing indicates that the patient has one or more genetic mutations associated with a neurodegenerative disease or central nervous system disorder.

  Neurodegenerative diseases are usually more common in the elderly. Thus, in some embodiments, the patient is 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or older.

2. Diseases Treated The methods disclosed herein can be used to treat patients with neurodegenerative diseases or disorders. Exemplary neurodegenerative diseases include Parkinson's disease (PD) and PD-related disorders, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and other dementias, Creutzfeldt-Jakob disease Such as prion disease, corticobasal degeneration, frontotemporal dementia, HIV-related cognitive impairment, mild cognitive impairment, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA) ), Friedreich's ataxia, Lewy body disease, Alpers disease, Batan's disease, brain / eye / face / skeletal syndrome, corticobasal degeneration, Gerstmann-Stroisler-Scheinker syndrome, Kool, Lee's disease, monocot Muscular atrophy, multiple system atrophy, multiple system atrophy due to orthostatic hypotension (Shy-Drager syndrome), multiple sclerosis (MS), neurodegeneration with iron accumulation in the brain, opsochronous myoclonus, posterior cortical atrophy, Primary progression ataxia, progression Supranuclear palsy, vascular dementia, progressive multifocal leukoencephalopathy, dementia with Lewy bodies, lacunar syndrome, hydrocephalus, Wernick-Korsakoff syndrome, postencephalitis dementia, cancer and cognition associated with chemotherapy Disorders and dementia, and depression-induced dementia and pseudodementia, include, but are not limited to.

  In some embodiments, the patient has a central nervous system disorder or is in need of neuroprotection. Exemplary conditions and / or patients include, have, or develop stroke, traumatic brain injury, spinal cord injury, post-traumatic stress syndrome, or a combination thereof. These include, but are not limited to, patients who may be affected.

a. Huntington's Disease The methods disclosed herein can be used to treat patients with Huntington's disease. Huntington's disease (HD) is a neurodegenerative disease that affects muscle regulation and causes cognitive decline and psychiatric problems. The chronic pathology of HD leads to a number of related impairments such as cognitive dysfunction, more specifically dysfunction in thinking and mental expression, changes in judgment and reasoning. HD is caused by an autosomal dominant mutation in either of the two copies of the huntingtin (HTT) gene in an individual. A part of this gene is a repetitive part called a trinucleotide repeat, and the length varies between individuals, and the length may change between generations. If the repeat is present in a healthy gene, dynamic mutations increase the number of repeats and can lead to gene defects. When the length of this repeat reaches a certain threshold, it produces an altered form of the protein called the mutant huntingtin protein (mHtt). The different functions of these proteins are responsible for the pathological changes that cause the symptoms of the disease. Huntington's disease mutations are genetically dominant and almost completely penetrant. Mutations in either of the human HTT genes can cause this disease. The physical manifestations of Huntington's disease can begin at any age from infancy to old age, but usually begin at age 35 to 44 (Walker et al., Lancet, 369 (9557): 218-28 (2007)). .

  In some embodiments, the patient exhibits one or more HD clinical symptoms, one or more HD molecular symptoms, or a combination thereof, as discussed herein and elsewhere. The clinical manifestations of HD are known in the art and include, but are not limited to, hallucinations, hypersensitivity, mood disorders, restlessness, delusions, paranoia, psychosis, suicidal thoughts, and attempts at suicide; chorea Not necessarily, facial movements such as frowning, head turning to shift eye positions, rapid and sudden, sometimes wild, cramping movements of arms, legs, face, and other body parts, Abnormal and / or unusual movements, such as slow and uncontrolled movements, erratic gait, unintended small or incomplete movements, and lack of coordination; but not limited to Cognitive and / or dementia-related symptoms such as disorientation and / or confusion, loss of judgment, memory loss, personality changes, and language changes; and anxiety, stress, tension, dysphagia, language Harm, rigidity, slow movement, tremor, malnutrition, and behavioral disorders and other symptoms such as weight loss and the like, but is not limited thereto. Neuropsychiatric features are a central component of this disease.

  Mutant Huntington's are expressed throughout the body and are associated with peripheral tissue abnormalities directly caused by such extra-brain expression. These abnormalities include muscle atrophy, heart failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy.

  Several studies have examined the prevalence of myriad symptoms in patients with Huntington's disease. Shiwach, Acta Psychiatr Scand, 90 (4): 241-6 (1994) report the results of a retrospective study of 110 patients with Huntington's disease in 30 families. The study found that the minimum lifetime prevalence of depression was 39%. The frequency of symptomatic schizophrenia was 9%, with a significant change in personality in 72% of the samples. Age at onset was highly variable. Some patients had some signs in the first 10 years, and some were asymptomatic until the age of 60.

  Rosenberg et al., J Med Genet., 32 (8): 600-4 (1995), describe a double-blind study in 33 individuals at risk for HD who applied for genetic testing. A series of neuropsychological tests covering attention, visual space, learning, memory, and planning function revealed significantly poorer cognitive function in gene carriers. Primarily, attention, learning, and planning functions were affected.

  Bamford et al., Neurology, 45 (10): 1867-73 (1995), reported a prospective analysis of neuropsychological performance and CT scans in 60 individuals with Huntington's disease. This study found that psychomotor skills show the most important and consistent decline among the assessed cognitive functions.

  Marshall et al., Arch Neurol., 64 (1): 116-21 (2007) reported that 29 carriers of HD mutations without clinical symptoms, 20 carriers of HD mutations with psychomotor symptoms, 34 patients with overt HD, and We have reported a study comparing 171 nonmutant controls. The mild motor symptom group and the manifest HD group had significantly higher scores for obsessive-compulsive behavior, interpersonal susceptibility, anxiety, paranoia, and psychosis compared to the nonmutant control group. The mild motor symptom group and the manifest HD group had significantly higher scores for obsessive-compulsive behavior, interpersonal susceptibility, anxiety, paranoia, and psychosis compared to the nonmutant control group. Asymptomatic mutation carriers had higher scores for anxiety, paranoia, and psychoticism compared to the non-mutation control group. The results showed that individuals in the preclinical stage of HD exhibited certain psychiatric symptoms, with additional symptoms appearing later in the course of the disease. Suicidal ideation is frequently found in Huntington's disease, and physicians should be aware of an increased risk of suicide in both asymptomatic and symptomatic patients (Walker et al., Lancet, 369 ( 9557): 218-28 (2007)).

  The mechanism underlying HD is discussed in Wang et al., Journal of Neuroscience, 31 (41): 14496-14507 (2011), and is discussed in more detail below. Studies show that mutant huntingtin (htt) -mediated toxicity in cells, mice, and humans is associated with loss of type 1 melatonin receptor (MT1). High levels of MT1 receptors were found in mitochondria in brains from wild-type mice, but much less in brains from HD mice, where melatonin inhibits mutant htt-induced caspase activation and MT1 receptors Expression was retained. Thus, in some embodiments, the compounds and compositions disclosed herein are for treating, for example, reducing, delaying or delaying mutant htt-induced caspase activation for treating one or more molecular symptoms of HD. An effective amount is administered to HD patients to inhibit; to reduce or prevent loss of MT1 receptor expression, particularly in the mitochondria of cells of the patient; or a combination thereof.

  In some embodiments, the patient exhibits one or more of the symptoms discussed herein, but does not exhibit all of the symptoms. Thus, in some embodiments, the patient does not have one or more of the conditions disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with HD by exhibiting clinical (eg, physical) symptoms of the disease. Excessive unintended movement of any part of the body is often the first clinical symptom. If these are sudden and the timing and distribution are random, they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely diagnosed first, and most typically only later, or when they progress further. Disease progression can be measured using the Unified Huntington's Disease Rating Scale, which provides an overall rating system based on motor, behavioral, cognitive and functional assessment (Huntington Study Group, Movement Disorders, 11 (2): 136-142 (1996)).

  Medical imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), and functional neuroimaging techniques, such as fMRI and PET, can supplement the analysis of physical symptoms, but typically It is not a single diagnosis.

  If you do not have a family history of HD, genetic testing can be used to confirm your physical diagnosis. Even before the onset of symptoms, genetic testing can determine if an individual or embryo carries an expanded copy of the trinucleotide repeat in the disease-causing HTT gene. The US Government-sponsored Genetics Invasion (Online Mendelian Inheritance in Man (OMIM) database) gives HD a phenotype # 143100. The gene / locus is huntingtin (HTT) and is located on chromosome 4p16.3 with the gene / locus MIM number 613004. Huntington's disease (HD) is a hereditary disease caused by an extended trinucleotide repeat (CAG) n encoding glutamine in the gene encoding huntingtin (HTT; 613004) on chromosome 4p16.3, so OMIM There is a 143100 number assigned to the entry. Genetic testing for HD consists of a blood test that counts the number of CAG repeats for each HTT allele.

  Cutoffs for genetic testing are given as follows according to De Die-Smulders et al., Human Reproduction Update, 19 (3): 304-315 (2013).

  Over 40 CAG repeats: Full Penetration Allele (FPA). "Positive test" or "positive result" generally means this case. A person who is positive for the disease will develop HD at some point in his life if he or she lives long enough for the disease to appear.

  36-39 repeats: incomplete or diminished penetrant allele (RPA). Symptoms may usually occur in late adulthood. At age 65, RPA patients have a maximum risk of developing symptoms of 60%, and at age 75 the risk of developing symptoms is 70%.

  Number of repeats 27-35: Intermediate allele (IA), or large normal allele. Although not associated with symptomatic disease in the individuals tested, it can spread to additional genetic traits and confer symptoms to offspring.

  Number of iterations less than 26: Not associated with HD.

  A positive result may be obtained decades before the onset of symptoms and is therefore considered different from clinical diagnosis. An individual who originally had a 50% chance of inheriting the disease could be told if the risk would be 100% or would be eliminated.

  Elsewhere, the number of repeats in normal individuals ranged from 9 to 36, with 37 or more in HD individuals (Duyao et al., Nat Genet., 4 (4): 387-92 (1993)).

  Thus, in some embodiments, the genetic test determines that the subject has a "positive result" or that the penetrant allele (RPA) is incomplete or diminished or that the intermediate allele is intermediate. It is determined to have a gene (IA) or a large normal allele, but the subject does not show any clinical symptoms or the clinical symptoms are too mild for a positive medical diagnosis. In certain embodiments, the subject has a "positive result" but does not show any clinical symptoms or the clinical symptoms are too mild for a positive medical diagnosis. Thus, in some embodiments, the compounds or compositions disclosed herein are administered prior to clinical diagnosis of HD.

b. Parkinson's Disease In certain embodiments, the disclosed compositions are used to treat patients with Parkinson's disease or suffering from Parkinsonism or Parkinson's syndrome. PD is a degenerative disease of the central nervous system. In some embodiments, the patient exhibits one or more clinical symptoms of PD, one or more molecular symptoms of PD, or a combination thereof, such as those discussed herein and elsewhere. The symptoms of PD are known in the art and have been reviewed by Jankovic et al., J. Neurol. Neurosurg. Psychiatr., 79 (4): 368-76 (2007). The motor symptoms of Parkinson's disease result from the death of dopaminergic cells in the substantia nigra, a region of the midbrain. The cause of cell death remains unknown. In the early stages of the disease, the most prominent symptoms are movement-related symptoms, including, but not limited to, tremor, stiffness, slow movement, difficulty walking and gaiting. In particular, the four motor symptoms characteristic of PD are tremor, stiffness, slow movement, and postural instability. The main motor symptoms are collectively referred to as Parkinsonism or "Parkinson's syndrome."

  Later, thought and behavioral problems occur, ranging from mild to severe, with dementia usually occurring at an advanced stage of the disease, with depression being the most common psychological symptom. Other common neuropsychiatric disorders include disorders of speech, cognition, mood, behavior, and thinking. Cognitive deficits that can occur early in the illness and before diagnosis include planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions and inhibition of inappropriate behavior, and associated sensory information. Dysfunction that can include problems with choice of; attentional instability and decreased cognitive speed; and memory impairment.

  Other symptoms include sensory, sleep, and emotional disorders. In fact, sleep and wakefulness disorders are one of the most common and disabling nonmotor symptoms of PD, affecting 90% of patients. (Videnovic et al., JAMA Neurol. Doi: 10.1001 / jamaneurol. 2013.6239, published online February 24, (2014)).

  A doctor's diagnosis of PD is typically made by a combination of medical history and neurological examination. Brain scans of people with PD are typically normal, but can be used to rule out disorders that can cause similar symptoms. Although there are no laboratory tests for PD, medical institutions are developing diagnostic criteria to facilitate and standardize the diagnostic process. See, for example, UK Parkinson's Disease Society Brain Bank, U.S. National Institute of Neurological Disorders and Stroke, and PD Society Brain Bank, which all provide criteria for diagnosing PD.

  Parkinson's disease is more common in the elderly, with most cases occurring after age 50. There is no cure for PD and it is most commonly managed using one combination of levodopa (usually in combination with a dopa decarboxylase inhibitor or COMT inhibitor), a dopamine agonist and a MAO-B inhibitor. There is no cure for PD, which is typically managed using one or a combination of levodopa (usually in combination with a dopa decarboxylase inhibitor or COMT inhibitor), a dopamine agonist and a MAO-B inhibitor. is there. Other common drugs include amantadine and anticholinergics to treat motor symptoms, clozapine to treat psychosis, cholinesterase inhibitors to treat dementia, and daytime sleepiness. Modafinil can be mentioned. Most commonly, surgery and deep brain stimulation can be used when the drug is no longer effective. Gene therapy, stem cell transplant, and neuroprotective agents are also being developed as treatment options for PD.

  In some embodiments, the patient exhibits one or more PD clinical symptoms, one or more ALS molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. In some embodiments, the patient exhibits one or more symptoms discussed herein, but not all. Thus, in some embodiments, the patient does not have one or more of the symptoms disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with PD by exhibiting clinical (eg, physical) symptoms of the disease. In some embodiments, the patient exhibits one or more symptoms discussed herein, but not all. Thus, in some embodiments, the patient does not have one or more of the symptoms disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with PD by exhibiting clinical (eg, physical) symptoms of the disease. In some patients, the appearance of sleep-related disorders precedes the clinical diagnosis of PD. Thus, in some embodiments, the compounds or compositions disclosed herein are administered prior to clinical diagnosis of PD.

c. Amyotrophic Lateral Sclerosis The methods disclosed herein can be used to treat patients with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a deadly motor neuron disease that affects primary and secondary motor neurons. ALS progression is characterized by motor neuron degeneration associated with demyelination in the anterior horn of the spinal cord. The etiology is only partially understood. Of 5-10% of familial cases, 20% have mutations in the superoxide dismutase 1 (SOD1) gene. This mutation is also present in 5% of sporadic cases (Rowland et al., New Engl J Med, 44: 1688-1700 (2001)). 3-4% of familial cases are due to pathogenic variants in the TDP-43 or FUS genes (Mackenzie et al., Lancet Neurol., 9: 995-1007 (2010)).

  In some embodiments, the patient exhibits one or more ALS clinical symptoms, one or more ALS molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. The clinical manifestations of ALS are known in the art. For example, the earliest symptoms of ALS are typically weakness and / or muscle wasting. Other early symptoms include dysphagia, seizures, or stiffness of the affected muscles; weakness affecting the arms or legs; and / or snorting nasal sounds, and possibly dementia.

  To be diagnosed with ALS, a patient must have signs and symptoms of both upper and lower motor neuron damage, not due to other causes. Diagnosis depends on the progressive degeneration of upper (UMN) and lower (LMN) motor neuron findings by history and examination and is 95% accurate when made by an experienced clinician (Gordon, Aging and Disease). , 4 (5): 295-310 (2013)). Electromyography can be used to identify a wide range of lower motor neuron disorders and to exclude other disorders such as multifocal motor neuropathy with conduction block. Cerebrospinal MRI eliminates conditions affecting UMN, such as cervical spondylosis. Occasionally, brain MRI shows bilateral signal changes within the corticospinal tract, a characteristic finding of ALS. The El Escorial criteria support standardization of diagnostics in clinical studies (Brooks et al., Amyotroph Lateral Scler Other Motor Neuron Disord, 1: 293-299 (2000)).

  Over time, patients experience increasing difficulty in moving, swallowing (dysphagia), speaking or forming words (dysarthria). Symptoms involving upper motor neurons include strained stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) such as overactivity of the gag reflex. Abnormal reflexes, commonly referred to as the Babinski sign, also indicate damage to upper motor neurons. Symptoms of mild motor neuron degeneration include muscle weakness and atrophy, muscle spasms, and momentary spasms of the muscle (fascic spasms) found under the skin. Degeneration of upper medullary motor neurons can cause exaggeration of motor development of emotions.

  However, the progression is patient-specific and ultimately renders most patients unable to walk or use their hands or arms. They also lose the ability to speak and swallow food, mostly ending up with portable ventilators. The rate of progression is a 12-item instrument managed as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). It can be measured using a result judgment method called "ALSFRS-R)".

  In a study based on an inter-clinician study, they assessed a 20% change in the slope of ALSFRS-R as clinically meaningful (Castrillo-Viguera et al., Amyotroph Lateral Scler, 11 (1-2): 178-80 (2010)). Thus, a composition can be administered to a patient in an amount effective to change the slope of the patient's ALSFRS-R by 1%, 5%, 10%, 15%, 20%, or more.

  In some embodiments, the patient's ALSFRS-R score is scored one or more times before and after the start of treatment. In some embodiments, the ALSFRS-R score requires days, weeks, months or more hours to improve.

  In some embodiments, the patient exhibits one or more ALS clinical symptoms, one or more ALS molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. In some embodiments, the patient exhibits one or more symptoms discussed herein, but not all. Thus, in some embodiments, the patient does not have one or more of the symptoms disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with ALS by exhibiting clinical (eg, physical) symptoms of the disease. In some embodiments, the patient exhibits one or more symptoms discussed herein, but not all. Thus, in some embodiments, the patient does not have one or more of the symptoms disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with ALS by exhibiting clinical (eg, physical) symptoms of the disease. In some patients, the appearance of sleep-related disorders precedes the clinical diagnosis of ALS. Thus, in some embodiments, the compounds or compositions disclosed herein are administered prior to clinical diagnosis of ALS. In some embodiments, genetic testing indicates that the patient has one or more genetic mutations associated with ALS.

d. Alzheimer's Disease The methods disclosed herein can be used to treat patients with Alzheimer's disease. Alzheimer's disease (AD) is the most common type of dementia. Although the cause and progression of AD are not completely understood, studies indicate that plaques and tangles in the brain play a pathophysiological role. Current treatments only support the symptoms of the disease, and there is no cure available that halts or reverses the progression of the disease.

  In some embodiments, the patient exhibits one or more AD clinical symptoms, one or more AD molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. The clinical manifestations of AD are known in the art. Although Alzheimer's disease varies from individual to individual, there are many common symptoms. Early symptoms are often mistaken for "age-related" concerns and signs of stress. One of the most common initial symptoms is loss of short-term memory. Moderate symptoms include, for example, increased memory loss and confusion; family and friend cognitive problems; narratives, favorite desires, continuous movements; multiple steps such as dressing Difficulty and / or lack of attention to hygiene and appearance. Severity symptoms include, for example, inability to recognize oneself or family members, inability to communicate, lack of control of the bowel or bladder, grunts, groans, moans, and / or help in any activity of daily life. And so on. Other common symptoms include confusion, irritability, aggression, mood swings, language impairment, and long-term memory loss. Gradually, they lose their physical function and eventually die.

  When AD is suspected, the diagnosis is usually confirmed by tests that assess behavioral and thinking abilities (eg, cognitive tests), followed by brain scans, if possible. Assessment of intellectual function, including neuropsychological tests such as the Memory Test and Mini Mental State Examination (MMSE), is widely used to assess cognitive impairment necessary for diagnosis (Waldemar et al., Eur J Neurol. 14 (1): e1-26 (2007)). Neurological examinations in early AD usually provide normal results, except for obvious cognitive impairment that may not be different from that due to other disease processes such as other causes of dementia.

  Examination of brain tissue can result in a definitive diagnosis. AD develops for unknown variable amounts of time before it becomes completely clear and can progress undiagnosed for years.

  In some embodiments, the patient exhibits one or more AD clinical symptoms, one or more ALS molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. In some embodiments, the patient exhibits one or more symptoms discussed herein, but not all. Thus, in some embodiments, the patient does not have one or more of the symptoms disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with AD by exhibiting clinical (eg, physical) symptoms of the disease. In some embodiments, the patient exhibits one or more symptoms discussed herein, but not all. Thus, in some embodiments, the patient does not have one or more of the symptoms disclosed herein or elsewhere.

  In some embodiments, the patient is medically diagnosed with AD by exhibiting clinical (eg, physical) symptoms of the disease. In some patients, the appearance of sleep-related disorders precedes the clinical diagnosis of AD. Thus, in some embodiments, the compounds or compositions disclosed herein are administered prior to clinical diagnosis of AD.

e. Traumatic Brain Injury In another particular embodiment, the disclosed compositions are used to treat patients suffering from traumatic brain injury (TBI). Traumatic brain injury occurs when an external mechanical force, typically head injury, causes brain dysfunction.

  Traumatic brain injury can have widespread physical and psychological consequences. Some signs or symptoms may appear immediately after the traumatic event, but may not appear until after days or weeks. Symptoms of TBI include loss of consciousness; dizziness, confusion, or loss of direction; problems with memory and concentration; headache, dizziness or loss of balance; nausea or vomiting; blurred vision, tinnitus, mouth discomfort Sensory problems such as unpleasant taste; sensitivity to light or sound; mood changes or mood swings; depression or anxiety; fatigue or drowsiness; sleep disorders; sleeping more than usual, furious, fighting , Or other abnormal behavior; slurredness; sleep unable to wake up; weakness or numbness in fingers or toes; loss of coordination; cramps or seizures, dilation of one or both eyes And / or transparent fluids flowing from the nose or ears, but are not limited thereto. In children, additional symptoms include changes in diet or parenting habits; continued crying and uncomfortable; unusual anger or anger; altered ability to pay attention; altered sleep habits; sad or depressed Mood; and / or loss of interest in favorite toys or activities.

  The TBI is a Glasgow Coma Scale that helps doctors or other emergency medical personnel to assess the initial severity of brain injury by tracking direction and checking the ability of a person to move their eyes and limbs. ) Can be used to diagnose. Talk consistency also provides an important clue. Ability is scored numerically, with higher scores indicating less severe injury. Imaging such as computed tomography (CT) and magnetic resonance imaging (MRI), as well as intracranial pressure monitoring can also be used to aid diagnosis by helping to identify the locality and extent of trauma. .

  Traditional treatments for TBI include administration of drugs such as diuretics, anticonvulsants and coma inducers; surgery to remove clotted blood, repair skull fractures, and / or relieve intracranial pressure. To be

IV. Methods for increasing tonic inhibition 4,5,6,7-Tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP), its derivatives or pharmaceuticals for increasing tonic inhibition There is also provided a method of using an acceptable salt. The method can be used to increase persistent depression in a patient with a disorder characterized by a deficiency or deficiency in persistent depression. Exemplary diseases include neurogenic diseases such as Fragile X Syndrome or Angelman Syndrome.

A. Treatment protocol
1. The disclosed methods for increasing sustained depression in a patient with sustained depression typically include, in a patient in need thereof, to increase the amount of THIP or a derivative thereof in order to increase sustained depression in the brain of the patient. Is administered.

  Neurodepression in the mammalian brain is mediated by two fast transmitters, glycine and γ-aminobutyric acid (GABA) (Jonas and Buzaki, Scholarpedia, 2 (9): 3286 (2007)). Glycine is the major inhibitory transmitter in the spinal cord and GABA is the major transmitter in higher brain regions. GABA released from presynaptic terminals can activate three different types of receptors, GABA receptors (GABA) A, B and C types. Neurodepression can be "transient" or "persistent." Transient inhibition is the short-lasting inhibition most frequently produced by GABAA receptor activation after action potentials in presynaptic interneurons. Among some long-lasting suppressive forms is the persistent GABA A conductance activated by surrounding GABA in the extracellular space. Persistent inhibition is mediated by molecularly and functionally specialized GABA A receptors that contain α6 or δ subunits and exhibit high affinity for GABA binding. THIP is a superagonist of the δ subunit-containing presynaptic and extrasynaptic GABAA receptors and mediates strong and persistent inhibitory conductance in the CNS (Brown et al., Br. J. Pharmacol., 136: 965-974. (2002), Glykys et al., J Physiol., 582: 1163-1178 (2007), Brown et al., Cell, 107: 477-487 (2001).

  Therefore, THIP can be used to enhance persistent inhibition in patients in need thereof.

  In vitro and animal model studies have shown that reduced persistent inhibition may be the root cause of some neurogenic disorders. For example, studies have shown that lower levels of GABA can lead to persistent suppression of cerebellar granule cells, the underlying cause of cerebellar ataxia in Angelman syndrome (Egawa et al., Science Translational Medicine). , 4: 163ra157 (2012)). Treatment with THIP (500 nM) increased persistent holding currents and reduced excitability of nuclear granule cells from a mouse model of Angelman syndrome to rescue the deficiency. THIP doses (1.25 mg / kg and 2.5 mg / kg) were effective in rescue cerebellar dysfunction in vivo (effective width or reduced stride hindfoot abduction without stride), but low Effective doses (eg 1.25 mg / kg) were effective in rescue cerebellar dysfunction without side effects (time reduction on rotarod).

  Studies have also shown that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex contributes to neuronal excitatory defects and behavioral abnormalities in fragile X syndrome (Olmos-Serrano et al. Dev. Neurosci., 33: 395-403 (2011), Olmos-Serrano et al., J. Neurosci., 30 (29): 9929-9938 (2010), Braat and Kooy, Drug Discovery Today, 19 (4): 510. -519 (2014)). In vitro experiments revealed that augmentation of the persistent inhibitory tendency with THIP rescued the decreased bioavailability of GABA and the decreased persistent current of BLm amygdala major neurons in Fmr1 knockout mice. Furthermore, THIP treatment reduces many fragile X phenotypes in Fmr1 knockout mice in vivo, such as reduced or attenuated hyperactivity (e.g., measured by locomotion and velocity) and reduced hypersensitivity to auditory stimuli. Improved.

2. Dose and Administration The disclosed methods of increasing tonic inhibition typically involve administering to a patient in need thereof an effective amount of THIP or a derivative thereof, preferably in more detail above. Pharmaceutically acceptable compositions such as those discussed.

  An effective or therapeutically effective amount is typically a dose sufficient to increase sustained inhibition of neurons in the patient's brain. In some embodiments, the methods reduce or prevent one or more neuropsychiatric morbidity or phenotype in a patient having a neurogenic disease or disorder discussed in more detail below. Thus, this amount may be effective to treat or prevent one or more symptoms of a neurogenic disease, or to provide a desired pharmacological and / or physiological effect, for example.

  The exact dosage depends on various factors such as patient-dependent variables (eg age, immune system health, clinical symptoms, etc.). Exemplary dosages, symptoms, pharmacological and physiological effects are discussed in more detail below.

  Particularly preferred embodiments include sustained release formulations. For example, the formulation may be suitable for administration once daily or less. In some embodiments, the composition is administered to the patient only once every 24-48 hours.

  The timing of administration of the composition depends on the formulation used and / or the route of administration. In some embodiments, administration of the composition will be given as a long-term therapeutic regimen by which a pharmacokinetic steady state is achieved.

  The preferred route of administration is transdermal, eg transdermal patches, which come into contact with the skin of the patient.

  In general, by way of example only, dosage forms useful in the disclosed methods are specific examples of preferred dosages of 0.1-1,000 mg, 1-200 mg, 5-175 mg, 7.5-150 mg, or 10-125. mg, or 12.5 to 150 mg, or 15 to 125 mg, or 17.5 to 100 mg, or 20 to 75 mg, or 22.5 to 60 mg, or 25 to 50 mg, and 1 mg, 5 mg, 10 It may include doses of mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, and 100 mg. Typically, such doses are administered to humans once, twice, or three times daily, or every other day.

  A typical oral dosage form preferably contains from about 2.5 mg to about 30 mg THIP. Preferably, THIP is in crystalline form. Further embodiments of the medicament include 2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg. , 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg, for example, an effective amount of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg. Including THIP. An exemplary embodiment is about 5 mg to about 20 mg of crystalline THIP, such as the hydrochloride salt of THIP. Typically, such doses are administered to humans once, twice, or three times daily, or every other day. In some embodiments, the total amount administered to a patient in 24 hours is 1 mg to 50 mg. In some embodiments, the patient is started at a low dose and the escalated dose of the drug is well tolerated by the patient.

  In the most preferred embodiment, the dose is effective to increase sustained inhibition without causing side effects in the patient. Side effects can include, for example, induced neuronal dysfunction and negative effects on thalamo-cortical network function such as increased frequency of seizures or excessive drowsiness or daytime somnolence. The animal model described above utilizes doses of 1.25 mg / kg to 3 mg / kg in mice. A dose of 1.25 mg / kg is preferred over a dose of 2.5 mg / kg as it has fewer side effects in certain animal models. Thus, in some embodiments, the dose is preferably from about 0.1 mg / kg to about 5 mg / kg with few or no side effects. Transformations known in the art can be used to extend the dose from mouse to human. Since this therapy typically involves administration during the time the patient is active, it is preferred that the dose not induce a sedative effect in the patient.

  In some embodiments, the effect of the composition on the patient is compared to a control. For example, the effect of the composition on a particular condition, pharmacological or physiological index can be compared to the condition of an untreated or pre-treated patient. In some embodiments, the symptom, pharmacological or physiological index is measured in the subject prior to treatment and one or more times after initiation of treatment. In some embodiments, the control is based on measuring symptoms, pharmacological or physiological indicators in one or more subjects (e.g., healthy subjects) who do not have the disease or condition being treated. Is the reference level or average that is used In some embodiments, the effects of treatment are compared to conventional treatments known in the art, such as one of those discussed herein.

B. Conditions, Symptoms, Patients and Diseases Treated In some embodiments, a patient in need of sustained suppression is a patient with a neurogenic disease. In some embodiments, the composition is administered in an amount effective to reduce or prevent one or more symptoms or phenotype of the disease. Diseases and conditions are discussed in more detail below.

1. Angelman Syndrome In some embodiments, the composition is used to treat a patient having Angelman syndrome. Angelman syndrome is a neurogenic disorder caused by a deletion or inactivation of a gene on maternally inherited chromosome 15, a paternal copy, which may be the normal sequence, is imprinted and silenced. Prader-Willi syndrome is caused by a similar deletion of paternally inherited genes and maternal imprinting.

  Symptoms of Angelman syndrome include the following: consistent symptoms in 100% of cases, frequent symptoms in 80% or more of cases, and symptoms associated with 20-80% of cases. Consistent symptoms include developmental delay; speech impairment, word use or minimal use; receptive and nonverbal communication skills higher than oral; motor or balance disorders; ataxia and / or gait usually Or tremor movements of the limbs; and often accompanied by flapping movements, hypermotor movements, short attention spans, or any combination thereof, frequent laughs / smiles, overt happiness, easily excited personality Specificity of behavior such as. Delayed, unbalanced growth of the head circumference, which usually causes microcephaly (absolute or relative) by age 2 years; seizures, usually under 3 years of age; and large, slow spike waves An abnormal EEG with a characteristic pattern accompanied by. Concomitant symptoms include poor vision, hypopigmented skin and eyes; protruding tongue; dysphagia / dysphagia; overactive tendon reflexes; eating disorders in infancy; lifting and bending arms while walking while walking; Jawbone; Hypersensitivity to heat; Large mouth, open teeth; Sleep disturbances; Frequent salivation; Tongue presenting; Love of water and attracting; Excessive chewing and muffling; Flat occipital region; Smooth Palms; loves water and is attracted; prefers curly things like paper and plastic; abnormal eating behaviors; obesity (older children); scoliosis; and constipation.

  Other common symptoms and methods of diagnosis of Angelman syndrome are discussed in Williams et al., American Journal of Medical Genetics, 140A: 413-418 (2006), which is incorporated by reference in its entirety. Incorporated herein

2. Fragile X syndrome compositions are used to treat patients with Fragile X syndrome (FXS). Fragile X syndrome is a neurogenic disorder. It is the most common monogenic causative autism, especially the genetic cause of intellectual disability in boys. FXS is associated with the expansion of CGG trinucleotide repeats affecting the fragile X mental retardation 1 (FMR1) gene on the X chromosome. In normal individuals, this DNA segment is repeated 5 to about 40 times. In people with Fragile X Syndrome, the CGG segment is repeated 200 times or more, leading to gene silencing. Loss or deficiency (deficiency) of FMR1 disrupts nervous system function and causes the signs and symptoms of Fragile X Syndrome.

  In addition to intellectual disability, salient features and symptoms of this syndrome include elongated faces, large or protruding ears, flat feet, larger testicles (giant testicles) and low muscle tone; recurrent otitis media (otitis media) and Sinusitis is common in early childhood; speech can be confusing or nervous; stereotypic behavior (eg, flapping hands) and atypical social development, especially shyness, Limited eye contact, memory problems and face cognitive difficulties; psychiatric problems such as attention deficit hyperactivity disorder, obsessive-compulsive disorder, mood disorders, dementia and anxiety disorders; distraction, hyperactivity, and vision , Hypersensitivity to auditory, tactile and olfactory stimuli, and patience; ophthalmic problems such as strabismus and amblyopia; neurological complications such as seizures; performing tasks that require a central executive system of working memory When doing Title; and premature menopause can be mentioned. Individuals with Fragile X Syndrome may also meet the diagnostic criteria for autism.

  Diagnosis of Fragile X Syndrome is made through genetic testing to determine the number of CGG repeats. Diagnosis of FXS requires at least 200 repeats, but men and women with 55-200 repeats of the CGG segment are said to have premutations in the FMR1 gene. However, most people with premutations are intellectually normal, and some individuals with premutations have less than normal amounts of FMRP. As a result, they may have milder versions of the physical symptoms of the disease and may experience emotional problems such as anxiety or depression.

  In some embodiments, the patient has Fragile X-Associated Tremor / Ataxia Syndrome (FXTAS)).

3. Rett Syndrome In some embodiments, the composition is used to treat a patient with Rett Syndrome, also referred to as cerebroatrophic hyperammonemia. Rett Syndrome is a neurodevelopmental disorder that most often affects women. Genetically, Rett syndrome is most typically caused by mutations in the gene MECP2, which is located on the X chromosome. This mutation can result sporadically or from germline mutations, but is typically not inherited. Mutations in the genes CDKL5 or FOXG1 have also been found in less than 10% of Rett syndrome. Rett's syndrome is initially diagnosed by clinical observation, but the diagnosis is definitive in the presence of a genetic defect in the MECP2 gene.

  The onset and severity of Rett syndrome varies from patient to patient. Prior to the onset of symptoms, the child generally appears to be growing and developing normally. Even in early childhood, early subtle abnormalities include loss of muscle tone (hypotonia), eating disorders and limb cramps. Then gradually, mental and physical symptoms begin to appear. Patients lose the intentional use of her hands and the ability to speak, and experience other early symptoms such as high or gait problems and diminished eye contact. The loss of functional use of the hand is followed by compulsive hand movements such as hand squeezing and fir. Since apraxia cannot exert its motor function, it can interfere with all physical movements, including gaze and speaking.

  Children with Rett syndrome have incontinence, dyspnea, respiratory arrest, hyperventilation and air swallowing, avoidance of eye gaze, lack of social / emotional mutual principality, and nonverbal behavior to control social interactions. It can also exhibit autistic-like behaviors such as marked disability, speech impairment and sensory problems. Other symptoms include toe walking, sleep problems, wide gait, bruxism and dyspnea, growth retardation, seizures, cognitive impairment, and apnea (breath arrest), possible height shortage, nutrition due to difficulty walking or swallowing. There are abnormal weights due to ataxia, hypotension, delayed or lack of walking ability, ataxia, microcephaly, gastrointestinal problems, some forms of convulsions, chorea and dystonia.

  Although there is currently no cure for Rett's syndrome, recovery of MECP2 using, for example, insulin-like growth factor-1 (IGF-1) holds promise in a mouse model (Tropea et al., Proc Natl Acad Sci US A., 106 (6): 2029-2034 (2009)). NMDA receptor antagonists have also shown promise. Symptoms include, for example, sleep aids, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (for self-harm), beta blockers (for long QT syndrome) and gastrointestinal dysfunction and malnutrition. It can also be treated with drugs that control

Four. Autism Spectrum In some embodiments, the composition comprises Asperger's syndrome, pervasive developmental disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), autism disorder, or another autism. Used to treat patients with spectrum.

  The autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder generally characterized by social disability, communication difficulties, and limited, repetitive and stereotypic behavioral patterns. Autism disorder, also called autism or classical ASD, is the most severe form of ASD. Children with classical ASD exhibit typically more severe social and verbal functions and recurrent behavioral deficits than children with other spectrum disorders. Often they also have mental retardation and / or seizures.

  Other conditions along the autism spectrum include Asperger syndrome and PDD-NOS. Asperger's syndrome (AS) is the mildest autism. Children with AS become more interested in a single object or subject. They often learn everything about their favorite subject and discuss it on an ongoing basis. In AS children, there is often no coordination.

  PDD-NOS symptoms can vary widely from child to child. Overall, children with PDD-NOS are better than children with impaired social interactions, autism, but not as much as verbal ability, Asperger's syndrome, or autism in children with Asperger's syndrome. It is characterized by fewer repetitive behaviors than children with autism and a later onset of age. There are no agreed criteria for diagnosing patients with PDD-NOS. Children may be diagnosed with PDD-NOS if they appear autistic to the assessment specialist but do not meet all the criteria for autism.

  Drug interventions are typically limited to the treatment of certain autism-related conditions such as anxiety, depression or obsessive-compulsive disorder. Antipsychotics can be used to treat behavioral problems. Seizures can be treated with one or more anticonvulsants. Drugs used to treat attention deficit disorder can be used to reduce impulsivity and overactivity in patients with autism spectrum disorders.

V. Combination Therapy In some embodiments, THIP or a derivative thereof is administered in combination with one or more additional active agents. Combination therapy can include co-administration of the active agents in the same mixture or in separate mixtures. Thus, in some embodiments, the pharmaceutical composition comprises two, three, or more active agents. Such formulations typically include an effective amount of THIP or derivative. Different active agents can have the same or different mechanisms of action. In some embodiments, the combination has an additive effect on the treatment of the disease or disorder. In some embodiments, the combination results in a synergistic effect on the treatment of the disease or disorder.

  The pharmaceutical composition can be formulated as a pharmaceutical dosage unit, also referred to as a unit dosage form.

  THIP or a derivative is a single activity administered to increase slow-wave sleep, increase sustained depression, and treat a neurogenic disorder, neurodegenerative disorder, central nervous system disorder, or a symptom or medical condition thereof. Or a THIP or derivative thereof for the treatment of neurodegenerative diseases, central nervous system disorders, or symptoms or conditions thereof to increase slow wave sleep and reduce or prevent cognitive dysfunction. It can be administered in combination with one active agent.

  In certain embodiments, the combination therapy comprises THIP or a derivative thereof and conventional treatment for one or more neurodegenerations as discussed herein or conventional treatment for increasing or enhancing neuroprotection. Include. Exemplary neuroprotective agents are known in the art and include, for example, glutamate antagonists, antioxidants and NMDA receptor stimulants. Other neuroprotective agents and treatments include caspase inhibitors, trophic factors, antiprotein aggregating agents, therapeutic hypothermia, and erythropoietin. In some embodiments, THIP or a derivative thereof is administered to the patient in combination with a treatment that increases nerve regeneration.

  In certain embodiments, THIP or a derivative thereof is combined with conventional therapeutic agents for Huntington's disease, such as dopamine inhibitors that help reduce abnormal behavior or movement, or drugs that control movement such as amantadine and tetrabenazine. Will be administered to patients in combination. Other drugs that help reduce chorea include neuroleptics and benzodiazepines. Compounds such as amantadine or rimacemide have shown preliminary positive results. In particular, in young cases, ataxia and rigidity can be treated with anti-Parkinson's disease drugs, and myoclonic hyperkalemia can be treated with valproic acid. Psychiatric conditions can be treated with drugs similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine are recommended for depression, while atypical antipsychotics are recommended for psychosis and behavioral problems.

  In another particular embodiment, THIP or a derivative thereof is a conventional treatment of Parkinson's disease such as levodopa (usually in combination with a dopa decarboxylase inhibitor or COMT inhibitor), a dopaminergic agonist or a MAO-B inhibitor. It is administered to patients in combination with. Other common agents that can be used in combination with the disclosed combinations are amantadine and anticholinergic agents for treating motor symptoms, clozapine for treating psychosis, cholinesterase for treating dementia. Inhibitors and modafinil for treating daytime sleepiness.

  In another particular embodiment, THIP or a derivative thereof is a conventional therapeutic agent for ALS, such as an anti-exitotoxin riluzole (RILUTEK®) (2-amino-6- (trifluoromethoxy) benzothiazole). Is administered to patients in combination with. Other medications, the most frequently used off-label drugs, and therapeutic interventions can alleviate the symptoms of ALS. Some treatments improve the quality of life and others prolong life. General ALS related therapies are reviewed in Gordon, Aging and Disease, 4 (5): 295-310 (2013), which is incorporated herein by reference in its entirety. Exemplary ALS treatments and interventions are provided in Table 1 below. The source is Gordon, Aging and Disease, 4 (5): 295-310 (2013).

Table 1: Treatment of ALS

Table 1 (continued):

Table 1 (continued):

  Bid = twice a day; IU = international units; qAM = every morning; qd = every day; qhs = every day; qt = bedtime; qid = four times a day; qnoon = noon every day; qxh = every x hours; SL = tongue Bottom; SR = sustained release; SSRI = serotonin specific reuptake inhibitor; tid = 3 times daily. *: It was shown to have a beneficial effect in ALS.

  Many other drugs have been tested in one or more clinical trials for efficacy ranging from ineffective to promising. Exemplary agents are reviewed in Carlesi et al., Archives Italiennes de Biologie, 149: 151-167 (2011). For example, in some embodiments, THIP or a derivative thereof has an excitatory activity such as (8-methyl-7H-1,3-dioxolo (2,3) benzodiazepine), cephalosporins such as ceftriaxone, or memantine. Drugs that reduce toxicity; coenzyme Q10, manganese porphyrin, KNS-760704 [(6R) -4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride, RPPX], or Drugs that reduce oxidative stress such as edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186); valproic acid, TCH346 (dibenzo (b, f) oxepin-10-ylmethyl-methylprop- 2-inylamine), histone deacetylase (HDAC) inhibitors such as minocycline or tauroursodeoxycholic acid (TUDCA), agents that reduce apoptosis; reduce neuroinflammation such as thalidomide and celastol Drugs; neurotrophic factors such as insulin-like growth factor 1 (IGF-1) or vascular endothelial growth factor (VEGF); heat shock protein inducers such as alumocromol; or autophagy inducers such as rapamycin or lithium It is administered to patients in combination.

  In another particular embodiment, THIP or a derivative thereof is used for acetylcholinesterase inhibitors such as tachyline, rivastigmine, galantamine or donepezil; or NMDA receptor antagonists such as memantine, or for AD such as antipsychotics. It is administered to patients in combination with conventional therapeutic agents.

  In some embodiments, the active agents include dietary changes with or without dietary supplements, exercise therapy, psychological and / or psychosocial counseling, physical therapy, occupational therapy, and speech therapy. It is administered in combination with combination therapy.

In some embodiments, the active agents include dietary changes with or without dietary supplements, exercise therapy, psychological and / or psychosocial counseling, physical therapy, occupational therapy, and speech therapy. It is administered in combination with combination therapy.
Aspects of the invention include the following.
[1] To increase the persistent inhibition of neurones in a patient, an effective amount of 4,5,6,7-tetrahydroisoxazolo is administered to a human patient having a neurodegenerative disease, a neurogenic disorder or a central nervous system disorder. (5,4-c) Pyridin-3-ol (THIP) or a derivative thereof, and administration of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, to suppress the persistent inhibition of neurons in a patient. How to increase.
[2] The method according to [1], wherein the patient has fragile X syndrome or fragile X-related tremor / ataxia syndrome (FXTAS).
[3] The method according to [1], wherein the patient has Angelman syndrome.
[4] To increase persistent depression of neurons in patients, an effective amount of 4,5,6,7-tetrahydroisoxazolo ( Fragile X syndrome or Fragile X related in a patient, comprising administering a pharmaceutical composition comprising 5,4-c) pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient. How to treat or prevent tremor / ataxia.
[5] To increase persistent inhibition of neurons in patients, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridine-3- A method for treating or preventing Angelman syndrome in a patient, comprising administering a pharmaceutical composition comprising all (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient.
[6] The method according to any one of [1] to [5], wherein the amount of THIP or a derivative thereof is not effective in causing a side effect in a patient.
[7] Increases slow wave sleep (SWS) and / or slow wave activity (SWA) in patients, normalizes sleep architecture, reduces secondary insomnia, non-rem (non-rapid eye movement (non-rapid eye movement)). movement)) (NREM) increase sleep, increase sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), increase or improve sleep efficiency, total wake time Neurodegeneration to shorten (TAA), reduce wakefulness (NWA), shorten sustained sleep latency (LPS), reduce premature wakefulness (WASO), or any combination thereof in patients. In patients with the disease or central nervous system disorders, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP) or its derivative and pharmaceutically acceptable Secondary insomnia in a patient, comprising administering a pharmaceutical composition comprising a potential carrier or excipient Method.
[8] An effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridine in patients with neurodegenerative diseases or central nervous system disorders to increase slow wave sleep in the patient. A method of increasing slow wave sleep in a patient, comprising administering a pharmaceutical composition comprising -3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient.
[9] Neurodegenerative diseases include Parkinson's disease (PD) and PD-related disorders, Alzheimer's disease (AD) and other dementias, prion diseases such as Creutzfeld-Jakob disease, corticobasal degeneration, and frontotemporal type. Dementia, HIV-related cognitive impairment, mild cognitive impairment, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body disease, Alpers disease, batans Disease, brain / eye / face / skeletal syndrome, corticobasal degeneration, Gerstmann-Stroisler-Scheinker syndrome, Cour, Leigh's disease, monocotyledonous atrophy, multiple system atrophy, multisystem due to orthostatic hypotension Atrophy (Shy-Drager syndrome), multiple sclerosis (MS), neurodegeneration with iron accumulation in the brain, opsochronous myoclonus, posterior cortical atrophy, primary ataxia, progressive supranuclear palsy, vascular dementia, Progressive multifocal white matter Disease, dementia with Lewy bodies, lacunar syndrome, hydrocephalus, Wernick-Korsakoff syndrome, dementia after encephalitis, cognitive impairment and dementia associated with cancer and chemotherapy, and depression-induced dementia and pseudodementia The method according to either [7] or [8], which is selected from the group consisting of
[10] The method according to [9], wherein the neurodegenerative disease is Huntington's disease.
[11] The method according to [9], wherein the neurodegenerative disease is Parkinson's disease.
[12] The method according to [9], wherein the neurodegenerative disease is amyotrophic lateral sclerosis.
[13] The method according to [9], wherein the neurodegenerative disease is Alzheimer's disease.
[14] The method according to any one of [7] to [13], wherein the patient has not been clinically diagnosed with a neurodegenerative disease.
[15] In any one of [7] to [13], wherein the patient has no significant physical symptoms of neurodegenerative disease or the clinical symptoms are too mild for a positive diagnosis of neurodegenerative disease. The method described.
[16] The method according to any one of [7] to [13], wherein the patient is clinically diagnosed with a neurodegenerative disease.
[17] The method according to any one of [1] to [16], wherein THIP or a derivative thereof is THIP or a pharmaceutically acceptable salt thereof.
[18] The method according to any one of [1] to [17], wherein THIP or a derivative thereof is the only active agent.
[19] The method according to any one of [1] to [18], wherein the pharmaceutical composition comprises an effective amount of THIP or a derivative thereof and one or more pharmaceutically acceptable carriers or excipients. .
[20] The method according to any one of [1] to [19], wherein the pharmaceutical composition is formulated for sustained release.
[21] The method according to any one of [1] to [20], wherein the pharmaceutical composition is administered once every 24 to 48 hours.
[22] The method according to any one of [1] to [21], wherein the pharmaceutical composition is administered transdermally.
[23] The method of [22], wherein the pharmaceutical composition is administered by contacting a transdermal patch containing the pharmaceutical composition with the skin of the patient.
[24] The method according to any one of [1] to [23], wherein the pharmaceutical composition is administered to the patient in the morning or the evening.
[25] The method according to any one of [1] to [24], wherein the daily dose of THIP or a derivative thereof is about 1 mg to 20 mg.
[26] The method according to any one of [1] to [24], wherein the pharmaceutical composition is administered to a patient intravenously.
[27] The method according to [26], wherein the patient is administered with a daily dose of THIP or a derivative thereof of about 0.001 mg to 30 mg.
[28] The method according to [27], wherein THIP or a derivative thereof is administered at a rate of 0.001 mg / kg / hour to 1 mg / kg / hour.

Claims (28)

  In order to increase the persistent inhibition of the patient's neurons, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5, 4-c) A method for increasing persistent depression of neurons in a patient, comprising administering a pharmaceutical composition comprising pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient. .   2. The method of claim 1, wherein the patient has Fragile X Syndrome or Fragile X Associated Tremor / Ataxia Syndrome (FXTAS).   The method of claim 1, wherein the patient has Angelman syndrome.   In patients with Fragile X syndrome or Fragile X-related tremor / ataxia syndrome, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4 -c) fragile X syndrome or fragile X-related tremor in a patient, comprising administering a pharmaceutical composition comprising pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient. A method of treating or preventing ataxia syndrome.   To increase the persistent inhibition of neurons in patients, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP Or a derivative thereof and a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a method for treating or preventing Angelman syndrome in a patient.   6. The method of any one of claims 1-5, wherein the amount of THIP or derivative thereof is not effective in causing side effects in the patient.   Increases slow wave sleep (SWS) and / or slow wave activity (SWA) in patients, normalizes sleep architecture, reduces secondary insomnia, non-REM (non-rapid eye movement) (NREM) Increase sleep, increase sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), increase or improve sleep efficiency, total wake time (TAA) To reduce the number of waking (NWA), the number of wakefulness (NWA), the duration of continuous sleep latency (LPS), the reduction of mid-wakefulness (WASO), or any combination thereof in a patient, due to a neurodegenerative disease or central nervous system. For patients with nervous system disorders, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or A method of treating secondary insomnia in a patient, comprising administering a pharmaceutical composition comprising an excipient.   To increase slow wave sleep in patients, an effective amount of 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridine-3-in patients with neurodegenerative diseases or central nervous system disorders is used. A method of increasing slow wave sleep in a patient comprising administering a pharmaceutical composition comprising all (THIP) or a derivative thereof and a pharmaceutically acceptable carrier or excipient.   Neurodegenerative diseases include Parkinson's disease (PD) and PD-related disorders, Alzheimer's disease (AD) and other dementias, prion diseases such as Creutzfeldt-Jakob disease, corticobasal degeneration, frontotemporal dementia, HIV-related cognitive impairment, mild cognitive impairment, motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body disease, Alpers disease, Batan disease, brain・ Eye / face / skeletal syndrome, corticobasal degeneration, Gerstmann-Stroisler-Shineker syndrome, Kour, Leigh disease, monocotyledonous atrophy, multiple system atrophy, multiple system atrophy due to orthostatic hypotension (Shy -Drager syndrome), multiple sclerosis (MS), neurodegeneration with iron accumulation in the brain, opsochronous myoclonus, posterior cortical atrophy, primary ataxia, progressive supranuclear palsy, vascular dementia, progressive polymorphism Focal leukoencephalopathy, Group consisting of dementia due to B-body, lacunar syndrome, hydrocephalus, Wernick-Korsakoff syndrome, post-encephalitis dementia, cognitive and dementia associated with cancer and chemotherapy, and depression-induced and dementia The method according to claim 7, which is selected from the group consisting of:   The method according to claim 9, wherein the neurodegenerative disease is Huntington's disease.   The method according to claim 9, wherein the neurodegenerative disease is Parkinson's disease.   The method according to claim 9, wherein the neurodegenerative disease is amyotrophic lateral sclerosis.   The method according to claim 9, wherein the neurodegenerative disease is Alzheimer's disease.   14. The method of any one of claims 7-13, wherein the patient has not been clinically diagnosed with a neurodegenerative disease.   14. The method of any one of claims 7-13, wherein the patient has no significant physical symptoms of neurodegenerative disease or the clinical symptoms are too mild for a positive diagnosis of neurodegenerative disease.   14. The method of any one of claims 7-13, wherein the patient has been clinically diagnosed with a neurodegenerative disease.   The method according to any one of claims 1 to 16, wherein THIP or a derivative thereof is THIP or a pharmaceutically acceptable salt thereof.   18. The method according to any one of claims 1 to 17, wherein THIP or a derivative thereof is the only active agent.   19. The method of any one of claims 1-18, wherein the pharmaceutical composition comprises an effective amount of THIP or a derivative thereof and one or more pharmaceutically acceptable carriers or excipients.   20. The method of any one of claims 1-19, wherein the pharmaceutical composition is formulated for sustained release.   21. The method of any one of claims 1-20, wherein the pharmaceutical composition is administered once every 24-48 hours.   22. The method of any one of claims 1-21, wherein the pharmaceutical composition is administered transdermally.   23. The method of claim 22, wherein the pharmaceutical composition is administered by contacting a transdermal patch containing the pharmaceutical composition with the skin of the patient.   24. The method of any one of claims 1-23, wherein the pharmaceutical composition is administered to the patient in the morning or evening.   25. The method of any one of claims 1-24, wherein the daily dose of THIP or a derivative thereof is about 1 mg to 20 mg.   25. The method of any one of claims 1-24, wherein the pharmaceutical composition is administered intravenously to the patient.   27. The method of claim 26, wherein the daily dose of THIP or a derivative thereof administered to the patient is about 0.001 mg to 30 mg.   28. The method of claim 27, wherein THIP or a derivative thereof is administered at a rate of 0.001 mg / kg / hour to 1 mg / kg / hour.